Endoscopic Staple Removal Combined with Biologic Therapy Enhances Postoperative Anastomotic Ulcer Healing in Crohn’s Disease: A Retrospective Cohort Study

Endoscopic Staple Removal Combined with Biologic Therapy Enhances Postoperative Anastomotic Ulcer Healing in Crohn’s Disease: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endoscopic Staple Removal Combined with Biologic Therapy Enhances Postoperative Anastomotic Ulcer Healing in Crohn’s Disease: A Retrospective Cohort Study Cheng Wei, Runpeng Zhao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8485301/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Objective This study aimed to evaluate the efficacy and safety of endoscopic staple removal combined with biologic therapy versus biologic therapy alone for postoperative anastomotic ulcers (PAUs) in Crohn's disease (CD). Methods A retrospective analysis was conducted on 77 CD patients diagnosed with PAUs (Rutgeerts score ≥ i2) following ileocolonic resection who received biologic therapy at Nanjing Second Hospital between January 2021 and August 2025. Based on the administration of endoscopic staple removal, patients were categorized into a combination therapy group (Group A, n = 29) and a biologic monotherapy group (Group B, n = 48). The primary endpoint was the endoscopic ulcer healing rate (Rutgeerts score i0-i1) at final follow-up. Secondary endpoints included clinical symptom remission rate, normalization rate of serum CRP (< 5 mg/L), endoscopic remission-free survival, and adverse events. Results Baseline characteristics were comparable between groups. The endoscopic healing rate was significantly higher in Group A than in Group B (82.76% vs. 25.00%, P < 0.001). Analysis of laboratory indicators, presented as median (IQR), demonstrated that Group A achieved significantly greater improvements in Alb (P = 0.014) and ESR (P = 0.013) at follow-up, whereas no significant inter-group differences were observed in the magnitude of change for CRP, Fc, or Hb. Survival analysis revealed a significantly shorter median time to endoscopic healing in Group A (9.2 months vs. not reached, Log-rank P = 0.007). Adverse event rates were comparable. Conclusion Endoscopic staple removal combined with biologic therapy is more effective than biologic therapy alone in promoting endoscopic mucosal healing for PAUs after CD surgery, with a comparable safety profile. Crohn's Disease Anastomotic Ulcer Endoscopic Staple Removal Biologics Mucosal Healing Retrospective Study Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Crohn's disease (CD) is a chronic, transmural inflammatory bowel disease characterized by recurrent inflammation throughout the gastrointestinal tract. Surgical intervention is ultimately required in approximately 70–80% of patients, with ileocolonic resection being the most frequently performed procedure [ 1 ]. Postoperative recurrence, however, remains a major challenge; endoscopic recurrence rates reach 70–90% within the first year after surgery in the absence of prophylactic therapy [ 2 ]. Postoperative anastomotic ulcers (PAUs) represent the earliest manifestation of disease recurrence and serve as critical predictors of subsequent clinical relapse [ 3 ]. Current management guidelines recommend postoperative pharmacological prophylaxis, particularly with biologic agents, which have demonstrated efficacy in reducing endoscopic recurrence rates and promoting mucosal healing [ 4 ]. Despite these advances, a substantial proportion of patients exhibit an inadequate response to biologic monotherapy. Surgical staples, acting as foreign bodies, have been hypothesized to contribute to persistent inflammation and impaired healing at the anastomotic site through mechanisms such as mechanical irritation, microcirculatory compromise, or immune activation [ 5 ]. This has prompted exploration of endoscopic staple removal as a potential adjunctive intervention. While several case series have reported promising outcomes with this approach [ 6 , 7 ], comparative evidence against standard biologic monotherapy remains scarce. The present study therefore represents one of the first comparative analyses designed to evaluate whether endoscopic staple removal, by addressing a potential perpetuating factor, can enhance the therapeutic efficacy of biologic agents in this clinical context. Materials and Methods 1. Study Population and Design A retrospective cohort study was conducted on CD patients treated at the Department of Gastroenterology, Nanjing Second Hospital, between January 2021 and August 2025. The study protocol received approval from the Institutional Review Board. Inclusion criteria were: (1) age ≥ 18 years; (2) diagnosis of CD confirmed by standard clinical, endoscopic, radiological, and pathological criteria [ 8 ]; (3) history of ileocolonic resection with anastomosis; (4) postoperative endoscopic evidence of anastomotic ulcers (Rutgeerts score ≥ i2); (5) initiation of biologic therapy (infliximab, adalimumab, ustekinumab, or vedolizumab) as postoperative prophylaxis. Exclusion criteria included: (1) complicated disease requiring urgent surgical intervention (e.g., stricture, fistula); (2) primary non-response to biologics; (3) pregnancy or lactation; (4) incomplete clinical data. Patients were classified into two groups based on endoscopic intervention: the combination therapy group (Group A, endoscopic staple removal plus biologics) and the biologic monotherapy group (Group B, biologics alone). Although this was a non-randomized assignment based on clinician discretion and patient factors, baseline characteristics were rigorously compared to ensure group comparability (Table 1 ). 2. Treatment Protocols Endoscopic Procedure All endoscopic interventions were performed by experienced endoscopists using dual-channel therapeutic endoscopes. Under direct visualization, residual staples were carefully grasped and removed using forceps or snares. The procedure was deemed successful when all visible staples were extracted without immediate complications. Biologic Therapy Both groups received standard biologic therapy according to approved protocols for CD. The choice of specific biologic agent was based on physician preference and individual patient characteristics. 3. Data Collection and Outcome Measures Demographic characteristics, disease history, surgical details, laboratory parameters, and endoscopic findings were extracted from electronic medical records. The primary endpoint was the endoscopic ulcer healing rate, defined as the achievement of a Rutgeerts score of i0 or i1 at the final follow-up endoscopy. Secondary endpoints included: (1) clinical remission rate (absence of CD-related complications including abdominal pain, diarrhea, or bleeding); (2) CRP normalization rate (CRP < 5 mg/L); (3) endoscopic remission-free survival (time from treatment initiation to the first endoscopic documentation of an i0/i1 score); (4) incidence of procedure-related and treatment-related adverse events. 4. Statistical Analysis Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). The normality of continuous variables was assessed using the Shapiro-Wilk test. Non-normally distributed variables were expressed as median (interquartile range, IQR) and compared between groups using the Mann-Whitney U test. Within-group comparisons (pre- vs. post-treatment) were performed using the Wilcoxon signed-rank test. Categorical variables were presented as frequencies and percentages, with between-group comparisons performed using the Chi-square or Fisher's exact tests as appropriate. Endoscopic remission-free survival was analyzed using the Kaplan-Meier method, with group comparisons conducted via the Log-rank test. A two-sided P-value < 0.05 was considered statistically significant. Results 1. Baseline Characteristics A total of 77 patients were enrolled, comprising 29 cases (37.66%) in Group A and 48 cases (62.34%) in Group B. No statistically significant differences were observed between the two groups regarding age, gender, preoperative symptoms, type of biologic agent used, or baseline Rutgeerts score (all P > 0.05), indicating good baseline comparability (Table 1 ). Table 1 Comparison of Baseline Characteristics Between the Two Groups [n(%)/x ± s] Characteristic (Group A, n = 29) (Group B, n = 48) χ²/t Value P Value Age (years) 40.52 ± 11.83 38.96 ± 11.57 0.553 0.581 Gender (Male/Female) 20(68.99%)/9(31.03%) 33(68.75%)/15(31.25%) 0.0004 0.983 Preoperative Symptoms 6.69 0.32 - Stenosis 11(37.93%) 19(39.58%) - Obstruction 11(37.93%) 13(27.08%) - Perforation 2(6.90%) 9(18.75%) - Intestinal Fistula 4(13.79) 6(12.50%) - Bleeding 0 1(2.08%) - Abdominal Pain 1(3.45%) 0 Type of Biologic Agent 0.41 0.89 - Infliximab 9(31.03%) 15(31.25%) - Adalimumab 2(6.90%) 5(10.42%) - Ustekinumab 17(58.62%) 27(56.25%) - Vedolizumab 1(3.45%) 1(2.08%) Baseline Rutgeerts Score 3.42 0.18 - i2 3(10.34%) 13(27.08%) - i3 20(68.07%) 29(60.42%) - i4 6(20.69%) 6(12.50%) 2. Analysis of Laboratory Indicators All laboratory indicators (CRP, Fc, ESR, Hb, Alb) were non-normally distributed (Shapiro-Wilk test, P < 0.05) and are therefore presented as median (IQR). Within-group comparisons were made using the Wilcoxon signed-rank test, and between-group comparisons using the Mann-Whitney U test. As shown in Table 2 , baseline levels of all indicators were comparable between groups (all P > 0.05). Within-group analysis revealed that the combination therapy group (A) experienced significant improvements from baseline in Hb (P = 0.002), CRP (P = 0.013), Alb (P = 0.014), and ESR (P = 0.001). In contrast, the monotherapy group (B) showed no significant within-group improvement for any laboratory indicator (all P > 0.05). Between-group comparison at the end of follow-up showed that the combination therapy group had significantly lower levels of Fc (P = 0.042) and ESR (P = 0.013), and higher Alb (P = 0.014) compared to the monotherapy group. No significant between-group differences were found in the final levels of CRP (P = 0.400) or Hb (P = 0.104). Table 2 Comparison of Laboratory Indicators Between the Two Groups [Median (IQR)] Indicator Group Before Treatment After Treatment Change (After-Before) P (Within-Group) P (Between-Groups, Post-Treatment) CRP Group A 2.66 (1.00, 8.00) 1.26 (0.50, 4.71) 1.40 (0.08, 4.34) 0.013 0.4 Group B 2.35 (2.00, 8.00) 1.76(0.87, 5.84) 0.80 (-1.66, 2.94) 0.228 Fc Group A 87.00 (23.50, 499.00) 38.00(23.00,100.00) 4.00 (-18.00, 389.00) 0.062 0.042 Group B 180.00(82.50,380.75) 92.50(30.00,298.75) 59.00 (-53.00, 231.25) 0.073 ESR Group A 11.00 (5.50, 20.00) 5.00 (3.50, 6.00) 6.00 (0.00, 15.50) 0.001 0.013 Group B 14.50 (4.25, 24.00) 6.00 (5.00, 16.50) 1.50 (-3.00, 14.00) 0.064 Hb Group A 128.00(114.50,141.50) 136.00(126.00,150.00) 6.00 (-0.50, 19.50) 0.002 0.104 Group B 127.00(115.00,138.00) 131.00(113.25,145.00) 4.50 (-11.75, 13.50) 0.424 Alb Group A 42.40 (38.95, 44.30) 45.20 (41.95, 46.55) 2.80 (-1.05, 4.75) 0.014 0.014 Group B 42.90 (40.15, 46.03) 42.25 (40.28, 44.48) -1.20 (-3.15, 1.98) 0.092 Note Data are presented as median (25th percentile, 75th percentile). The ‘Change’ value represents the median (IQR) of the difference between post- and pre-treatment values. Within-group comparisons were performed using the Wilcoxon signed-rank test. Between-group comparisons of post-treatment values were performed using the Mann-Whitney U test. Bold indicates P < 0.05. 3. Efficacy Evaluation Primary Endpoint At the end of follow-up, the endoscopic ulcer healing rate (Rutgeerts score i0-i1) was 82.76% (24/29) in Group A, significantly higher than the 25.00% (12/48) observed in Group B (χ²=16.843, P < 0.001) (Table 3 ). Table 3 Comparison of Primary and Secondary Endpoints Between the Two Groups [n (%)] Indicator Combined Treatment Group (Group A, n = 29) Biologic Monotherapy Group (Group B, n = 48) χ² Value P Value Endoscopic Ulcer Healing Rate (i0-i1) 24(82.76) 12(25.00%) 24.98 < 0.001 Clinical Remission Rate (No Complications) 26(89.66) 45(93.75) 0.478 0.490 CRP Normalization Rate (< 5 mg/L) 23(79.31%) 34(70.83%) 0.650 0.420 Secondary Endpoints: Clinical remission rate was 89.66% (26/29) in Group A and 93.75% (45/48) in Group B, with no statistically significant difference (χ²=0.478, P = 0.490). CRP normalization rate was 79.31% (23/29) in Group A and 70.83% (34/48) in Group B; the difference was not statistically significant (χ²=0.650, P = 0.420). 4. Survival Analysis Kaplan-Meier analysis demonstrated significantly superior endoscopic remission-free survival in Group A compared to Group B (Log-rank P = 0.007). The median time to endoscopic healing was 9.2 months in Group A, whereas it was not reached in Group B by the end of the study period. The cumulative healing rates at 6 months were 41.4% in Group A versus 16.7% in Group B, and at 12 months were 62.1% versus 29.2%, respectively (Fig. 1 ). Kaplan-Meier curves show the cumulative probability of not achieving endoscopic ulcer healing over time. Endoscopic healing was defined as a Rutgeerts score of i0 or i1. Patients in the combination therapy group (black line, n = 29) underwent endoscopic staple removal in addition to biologic therapy, while patients in the monotherapy group (blue line, n = 48) received biologic therapy only. The difference between the groups was statistically significant by the log-rank test (P = 0.007). The hazard ratio for ulcer healing, derived from a Cox regression analysis, was 2.15 (95% CI: 1.32–3.51), indicating a significantly accelerated healing rate in the combination therapy group. The table beneath the plot displays the number of patients at risk in each group at sequential time points, with follow-up time in months. 5.Representative Endoscopic Findings Figure 2 Colonoscopic view of the anastomotic site in a patient with Crohn’s disease, 6 months after surgical resection of diseased bowel segments and subsequent ustekinumab therapy. The image demonstrates Rutgeerts score grade i3 anastomotic ulceration at the ileocolic anastomosis, with a visible stapler staple adjacent to the ulcer. The staple was removed endoscopically during this follow-up examination. Figure 3 Colonoscopic view of the same anastomotic site 9 months after staple removal (15 months post-surgical resection and ustekinumab initiation). The anastomotic ulceration has resolved substantially, with only mild mucosal hyperemia noted at the anastomotic line. Figure 4 Colonoscopic view of the ileocolic anastomosis in a patient with Crohn’s disease, 6 months after surgical bowel resection and maintenance infliximab therapy. The image demonstrates a large anastomotic ulceration (Rutgeerts score i4) accompanied by anastomotic stenosis, with a visible surgical staple adjacent to the lesion. The staple was removed endoscopically during this follow-up evaluation. Figure 5 Colonoscopic view of the same anastomotic site at the time of staple removal (concurrent with Fig. 4 ), confirming the extent of the grade i4 ulceration and stenosis. Figure 6 Colonoscopic view of the anastomotic site 15 months after staple removal (21 months post-surgical resection and infliximab initiation). The large anastomotic ulceration has resolved completely, with only mild mucosal hyperemia present at the anastomotic line. 6. Safety Assessment All endoscopic staple removal procedures were successfully completed without major complications such as perforation or significant bleeding. Two patients (6.9%) in Group A experienced transient mild abdominal pain or melena that resolved spontaneously without intervention. The incidence of biologic therapy-related adverse events was low and comparable between groups (3.4% vs. 6.3%, P = 0.589). Discussion In this retrospective cohort study, endoscopic staple removal combined with biologic therapy was found to significantly improve endoscopic outcomes in CD patients with PAUs compared to biologic therapy alone. The combination approach yielded substantially higher rates of mucosal healing and a markedly shorter time to endoscopic remission. Analysis of serial laboratory indicators provided compelling objective evidence reinforcing the therapeutic advantage of the combined strategy. A key distinction emerged from the within-group analysis: statistically significant improvements from baseline across multiple parameters—including Hb, CRP, Alb, and ESR—were observed exclusively in the combination therapy group. This pattern suggests that endoscopic staple removal may potentiate or accelerate the systemic anti-inflammatory and reparative effects mediated by biologic agents. Moreover, direct between-group comparison at the endpoint revealed that the combination therapy group achieved significantly more favorable levels of Fc, ESR, and Alb. The consistent and significant improvement in serum albumin, a marker of nutritional status and chronic inflammatory burden, implies that benefits of the combined strategy may extend beyond local mucosal healing to ameliorate systemic sequelae of CD [ 9 ]. Potential Mechanisms These findings lend strong support to the pathophysiological hypothesis that retained surgical staples act as foreign bodies, perpetuating local inflammation and impairing tissue repair through mechanisms such as persistent mechanical irritation, microcirculatory disturbance, and activation of innate immune pathways [ 5 , 10 ]. The observation that significant reductions in systemic (CRP, ESR) and gut-specific (fecal calprotectin) inflammatory markers occurred predominantly within the combination group provides tangible laboratory evidence for this mechanistic premise. The survival analysis further underscores the clinical impact of this intervention. Achieving early endoscopic remission is of paramount importance, as it has been consistently linked to superior long-term outcomes in CD, including a reduced risk of clinical relapse and re-operation [ 11 ]. The decision for endoscopic intervention was based on endoscopist preference rather than randomization, introducing a potential for selection bias. However, the balanced baseline characteristics between the two groups strengthen the validity of the comparative analysis. The dissociation between significant improvements in endoscopic/laboratory endpoints and the non-significant difference in clinical remission rates is noteworthy. This phenomenon has been recognized in postoperative CD management, where symptomatic response may lag behind objective mucosal healing [ 12 ]. Furthermore, our definition of clinical remission, while clinically practical, may be less sensitive than validated disease activity indices for detecting subtle symptomatic changes. This underscores the paramount importance of endoscopic evaluation as the gold standard for assessing treatment efficacy in the postoperative setting. The safety profile of endoscopic staple removal in this cohort was excellent, aligning with prior reports establishing its technical feasibility and safety when performed by experienced endoscopists [ 6 , 7 ]. Limitations Several limitations of this study must be acknowledged. First, the retrospective, non-randomized design carries an inherent risk of selection and confounding bias. Second, although the sample size was sufficient to detect a significant difference in the primary endpoint, the relatively small number of patients in the combination therapy group may have limited the statistical power for some secondary outcomes. The use of a non-validated clinical endpoint and the lack of central, blinded review for endoscopic scores are additional constraints. Future prospective, randomized controlled trials with standardized protocols, central endoscopic reading, and incorporation of patient-reported outcomes are warranted to confirm these findings and precisely define the role of endoscopic staple removal in the postoperative management algorithm for CD. Conclusion This study provides evidence that endoscopic staple removal combined with biologic therapy is significantly more effective than biologic therapy alone in achieving endoscopic mucosal healing for PAUs in CD patients, with a comparable safety profile. The combination approach resulted in higher healing rates, accelerated time to endoscopic remission, and was associated with significant improvements in several key laboratory indicators which were not observed with monotherapy. These findings support the concept that foreign body removal may enhance the efficacy of biological therapy in the postoperative setting. While confirmation through prospective trials is warranted, endoscopic staple removal represents a promising adjunctive strategy for managing postoperative recurrence in CD. Declarations Author Contributions: Wei Cheng: Conceptualization, Methodology, Formal Analysis, Investigation, Data Curation, Writing – Original Draft, Visualization. Zhao Runpeng: Conceptualization, Methodology, Investigation, Data Curation, Writing – Review & Editing. All authors have read and agreed to the published version of the manuscript. Funding: Not applicable. Data Availability Statement: The datasets generated during and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request. Ethics Approval and Consent to Participate: This study was approved by the Institutional Review Board of Nanjing Second Hospital. All procedures performed were in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments. The need for informed consent was waived by the Institutional Review Board of Nanjing Second Hospital due to the retrospective nature of the study. Consent for Publication: Not applicable. Conflict of Interest: The authors declare that they have no conflict of interest. References Rivière P, Vermeire S, Irles-Depe M, et al. Rates of postoperative recurrence of Crohn's disease and effects of immunosuppressive and biologic therapies. Clin Gastroenterol Hepatol. 2021;19(4):713–21. 10.1016/j.cgh.2020.02.035 . Buisson A, Chevaux JB, Allen PB, Bommelaer G, Peyrin-Biroulet L. Review article: the natural history of postoperative Crohn's disease recurrence. Aliment Pharmacol Ther. 2012;35(6):625–33. 10.1111/j.1365-2036.2012.05000.x . De Cruz P, Kamm MA, Hamilton AL, et al. Crohn's disease management after intestinal resection: a randomised trial. Lancet. 2015;385(9976):1406–17. 10.1016/S0140-6736(14)61908-5 . Ma C, Battat R, Parker CE, et al. Update on C-reactive protein and fecal calprotectin: are they accurate measures of disease activity in Crohn's disease? Expert Rev Gastroenterol Hepatol. 2019;13(4):319–30. 10.1080/17474124.2019.1568241 . Li Y, Stocchi L, Liu X, et al. Association of Surgical Stapler Use with Anastomotic Complications in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Dis Colon Rectum. 2023;66(3):e107–18. 10.1097/DCR.0000000000002263 . Shen B, Kochhar G, Navaneethan U, et al. Endoscopic removal of staples in patients with Crohn's disease and anastomotic ulcers: a multicenter experience. Gastrointest Endosc. 2019;89(2):380–e3871. 10.1016/j.gie.2018.08.038 . Yamamoto T, Shimoyama T, Umegae S, Matsumoto K. Endoscopic removal of anastomotic staples in patients with Crohn's disease. Gastroenterol Rep (Oxf). 2018;6(2):150–1. 10.1093/gastro/goy004 . Gomollón F, Dignass A, Annese V, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 1: Diagnosis and Medical Management. J Crohns Colitis. 2017;11(1):3–25. 10.1093/ecco-jcc/jjw168 . D'Amico F, Rubin DT, Kotze PG, et al. International Consensus on the Prevention of Postoperative Recurrence in Crohn's Disease: Key Concepts and Advanced Interventions. A Delphi Study. J Crohns Colitis. 2023;17(8):1292–305. 10.1093/ecco-jcc/jjad033 . Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn's disease. Clin Gastroenterol Hepatol. 2015;13(6):1042–e10502. 10.1016/j.cgh.2013.09.006 . Shah SC, Colombel JF, Sands BE, Narula N. Systematic review with meta-analysis: mucosal healing is associated with improved long-term outcomes in Crohn's disease. Aliment Pharmacol Ther. 2016;43(3):317–33. 10.1111/apt.13475 . Walsh AJ, Bryant RV, Travis SP. Current best practice for disease activity assessment in IBD. Nat Rev Gastroenterol Hepatol. 2016;13(10):567–79. 10.1038/nrgastro.2016.128 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 24 Feb, 2026 Reviewers agreed at journal 12 Feb, 2026 Reviewers agreed at journal 12 Feb, 2026 Reviewers invited by journal 05 Feb, 2026 Editor assigned by journal 04 Feb, 2026 Editor invited by journal 12 Jan, 2026 Submission checks completed at journal 09 Jan, 2026 First submitted to journal 09 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8485301","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587586603,"identity":"72dd5d19-4866-4126-96a0-b9b7075d6828","order_by":0,"name":"Cheng Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYFACxvbPf//UyPGzNx988AHI52NgYCaghbmNgbfhmLFkz7FkwxkMDBJshLWwg7QwJ264kWMmzUOMFoPjB9seSO5gM5ZsAGqxqThcx8befNiAocYmGqeWM4ntBoZnZOT4GY4VW+ecOSzBxnMsOYHhWFpuAw4tZjcYGyQS2IC2NDZvvJ3bBtQikWN8gLHhMH4tB9iAfjnMYCBtSaSWNsnGNqCWYyxG0oxQLQn4tNifSWw2ZjgDCmS2ZMOeM+mSbUC/GCTg8Ytk+/GHjxkqgFEp//jggx8V1vzAOD0s8aHGBqcWHCCBNOWjYBSMglEwCtAAANRCWuVSsjYdAAAAAElFTkSuQmCC","orcid":"","institution":"Nanjing Second Hospital","correspondingAuthor":true,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Wei","suffix":""},{"id":587586606,"identity":"a1f88c31-1dc8-4d9a-900e-9b45fea3bc57","order_by":1,"name":"Runpeng Zhao","email":"","orcid":"","institution":"Nanjing Jiangning Hospital","correspondingAuthor":false,"prefix":"","firstName":"Runpeng","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2025-12-31 03:08:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8485301/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8485301/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102297641,"identity":"aaa96aa9-c82e-4ded-ac0b-879cbece19c0","added_by":"auto","created_at":"2026-02-10 10:28:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39657,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic Staple Removal Combined with Biologics Accelerates Ulcer Healing Compared to Biologics Alone.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8485301/v1/a38920c3288f5c85bac615f1.png"},{"id":102239717,"identity":"c0eaf4c4-ab2c-4bfe-a946-e6297a780414","added_by":"auto","created_at":"2026-02-09 16:46:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":249968,"visible":true,"origin":"","legend":"\u003cp\u003eColonoscopic view of the anastomotic site in a patient with Crohn’s disease, 6 months after surgical resection of diseased bowel segments and subsequent ustekinumab therapy. The image demonstrates \u003cstrong\u003eRutgeerts score grade i3 anastomotic ulceration\u003c/strong\u003e at the ileocolic anastomosis, with a visible stapler staple adjacent to the ulcer. The staple was removed endoscopically during this follow-up examination.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8485301/v1/94ac2e1f69eb5b98baa81bfc.png"},{"id":102239720,"identity":"710a75f0-dbb3-4755-9126-513e6fa8691f","added_by":"auto","created_at":"2026-02-09 16:46:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":225569,"visible":true,"origin":"","legend":"\u003cp\u003eColonoscopic view of the same anastomotic site 9 months after staple removal (15 months post-surgical resection and ustekinumab initiation). The anastomotic ulceration has resolved substantially, with only mild \u003cstrong\u003emucosal hyperemia\u003c/strong\u003e noted at the anastomotic line.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8485301/v1/4fc34f0c7a8dbb3ce680cb1d.png"},{"id":102239719,"identity":"020554a0-ca3e-4189-8f86-699ff22349a0","added_by":"auto","created_at":"2026-02-09 16:46:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":329162,"visible":true,"origin":"","legend":"\u003cp\u003eColonoscopic view of the ileocolic anastomosis in a patient with Crohn’s disease, 6 months after surgical bowel resection and maintenance infliximab therapy. The image demonstrates a \u003cstrong\u003elarge anastomotic ulceration (Rutgeerts score i4)\u003c/strong\u003e accompanied by anastomotic stenosis, with a visible surgical staple adjacent to the lesion. The staple was removed endoscopically during this follow-up evaluation.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8485301/v1/bfb918651cded3fca65919c0.png"},{"id":102239721,"identity":"ec0a316a-1782-463d-b103-63dda38b1d27","added_by":"auto","created_at":"2026-02-09 16:46:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":310472,"visible":true,"origin":"","legend":"\u003cp\u003eColonoscopic view of the same anastomotic site at the time of staple removal (concurrent with Figure 4), confirming the extent of the grade i4 ulceration and stenosis.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8485301/v1/f1ca2534083c0d00ed3a48ff.png"},{"id":102239722,"identity":"f696bd16-0023-4750-a7b5-6c4a595d7127","added_by":"auto","created_at":"2026-02-09 16:46:54","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":350616,"visible":true,"origin":"","legend":"\u003cp\u003eColonoscopic view of the anastomotic site 15 months after staple removal (21 months post-surgical resection and infliximab initiation). The large anastomotic ulceration has resolved completely, with only mild \u003cstrong\u003emucosal hyperemia\u003c/strong\u003e present at the anastomotic line.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8485301/v1/0b494934f692475832733c20.png"},{"id":103056264,"identity":"fe3ebe50-64ce-43b9-8661-8c5b0c5eec92","added_by":"auto","created_at":"2026-02-20 09:00:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2993428,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8485301/v1/262135a8-f5d6-4c02-b7de-b3695ccd4d09.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Endoscopic Staple Removal Combined with Biologic Therapy Enhances Postoperative Anastomotic Ulcer Healing in Crohn’s Disease: A Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCrohn's disease (CD) is a chronic, transmural inflammatory bowel disease characterized by recurrent inflammation throughout the gastrointestinal tract. Surgical intervention is ultimately required in approximately 70\u0026ndash;80% of patients, with ileocolonic resection being the most frequently performed procedure [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Postoperative recurrence, however, remains a major challenge; endoscopic recurrence rates reach 70\u0026ndash;90% within the first year after surgery in the absence of prophylactic therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePostoperative anastomotic ulcers (PAUs) represent the earliest manifestation of disease recurrence and serve as critical predictors of subsequent clinical relapse [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Current management guidelines recommend postoperative pharmacological prophylaxis, particularly with biologic agents, which have demonstrated efficacy in reducing endoscopic recurrence rates and promoting mucosal healing [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite these advances, a substantial proportion of patients exhibit an inadequate response to biologic monotherapy.\u003c/p\u003e \u003cp\u003eSurgical staples, acting as foreign bodies, have been hypothesized to contribute to persistent inflammation and impaired healing at the anastomotic site through mechanisms such as mechanical irritation, microcirculatory compromise, or immune activation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This has prompted exploration of endoscopic staple removal as a potential adjunctive intervention. While several case series have reported promising outcomes with this approach [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], comparative evidence against standard biologic monotherapy remains scarce. The present study therefore represents one of the first comparative analyses designed to evaluate whether endoscopic staple removal, by addressing a potential perpetuating factor, can enhance the therapeutic efficacy of biologic agents in this clinical context.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\n\u003ch3\u003e1. Study Population and Design\u003c/h3\u003e\n\u003cp\u003eA retrospective cohort study was conducted on CD patients treated at the Department of Gastroenterology, Nanjing Second Hospital, between January 2021 and August 2025. The study protocol received approval from the Institutional Review Board.\u003c/p\u003e \u003cp\u003eInclusion criteria were: (1) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (2) diagnosis of CD confirmed by standard clinical, endoscopic, radiological, and pathological criteria [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; (3) history of ileocolonic resection with anastomosis; (4) postoperative endoscopic evidence of anastomotic ulcers (Rutgeerts score\u0026thinsp;\u0026ge;\u0026thinsp;i2); (5) initiation of biologic therapy (infliximab, adalimumab, ustekinumab, or vedolizumab) as postoperative prophylaxis.\u003c/p\u003e \u003cp\u003eExclusion criteria included: (1) complicated disease requiring urgent surgical intervention (e.g., stricture, fistula); (2) primary non-response to biologics; (3) pregnancy or lactation; (4) incomplete clinical data.\u003c/p\u003e \u003cp\u003ePatients were classified into two groups based on endoscopic intervention: the combination therapy group (Group A, endoscopic staple removal plus biologics) and the biologic monotherapy group (Group B, biologics alone). Although this was a non-randomized assignment based on clinician discretion and patient factors, baseline characteristics were rigorously compared to ensure group comparability (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003e2. Treatment Protocols\u003c/h3\u003e\n\u003cp\u003e \u003cstrong\u003eEndoscopic Procedure\u003c/strong\u003e \u003cp\u003eAll endoscopic interventions were performed by experienced endoscopists using dual-channel therapeutic endoscopes. Under direct visualization, residual staples were carefully grasped and removed using forceps or snares. The procedure was deemed successful when all visible staples were extracted without immediate complications.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eBiologic Therapy\u003c/strong\u003e \u003cp\u003eBoth groups received standard biologic therapy according to approved protocols for CD. The choice of specific biologic agent was based on physician preference and individual patient characteristics.\u003c/p\u003e \u003c/p\u003e\n\u003ch3\u003e3. Data Collection and Outcome Measures\u003c/h3\u003e\n\u003cp\u003eDemographic characteristics, disease history, surgical details, laboratory parameters, and endoscopic findings were extracted from electronic medical records.\u003c/p\u003e \u003cp\u003eThe primary endpoint was the endoscopic ulcer healing rate, defined as the achievement of a Rutgeerts score of i0 or i1 at the final follow-up endoscopy.\u003c/p\u003e \u003cp\u003eSecondary endpoints included: (1) clinical remission rate (absence of CD-related complications including abdominal pain, diarrhea, or bleeding); (2) CRP normalization rate (CRP\u0026thinsp;\u0026lt;\u0026thinsp;5 mg/L); (3) endoscopic remission-free survival (time from treatment initiation to the first endoscopic documentation of an i0/i1 score); (4) incidence of procedure-related and treatment-related adverse events.\u003c/p\u003e\n\u003ch3\u003e4. Statistical Analysis\u003c/h3\u003e\n\u003cp\u003eStatistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). The normality of continuous variables was assessed using the Shapiro-Wilk test. Non-normally distributed variables were expressed as median (interquartile range, IQR) and compared between groups using the Mann-Whitney U test. Within-group comparisons (pre- vs. post-treatment) were performed using the Wilcoxon signed-rank test. Categorical variables were presented as frequencies and percentages, with between-group comparisons performed using the Chi-square or Fisher's exact tests as appropriate. Endoscopic remission-free survival was analyzed using the Kaplan-Meier method, with group comparisons conducted via the Log-rank test. A two-sided P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\n\u003ch3\u003e1. Baseline Characteristics\u003c/h3\u003e\n\u003cp\u003eA total of 77 patients were enrolled, comprising 29 cases (37.66%) in Group A and 48 cases (62.34%) in Group B. No statistically significant differences were observed between the two groups regarding age, gender, preoperative symptoms, type of biologic agent used, or baseline Rutgeerts score (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), indicating good baseline comparability (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Baseline Characteristics Between the Two Groups [n(%)/x\u0026thinsp;\u0026plusmn;\u0026thinsp;s]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(Group A, n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(Group B, n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eχ\u0026sup2;/t Value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.52\u0026thinsp;\u0026plusmn;\u0026thinsp;11.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.96\u0026thinsp;\u0026plusmn;\u0026thinsp;11.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.581\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (Male/Female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(68.99%)/9(31.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33(68.75%)/15(31.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.983\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative Symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(37.93%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(39.58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Obstruction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(37.93%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(27.08%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Perforation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(6.90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9(18.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Intestinal Fistula\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(13.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(12.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(2.08%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Abdominal Pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(3.45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of Biologic Agent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Infliximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(31.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(31.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Adalimumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(6.90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(10.42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Ustekinumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(58.62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27(56.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Vedolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(3.45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(2.08%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline Rutgeerts Score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- i2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(10.34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(27.08%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- i3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(68.07%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29(60.42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- i4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(20.69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(12.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e2. Analysis of Laboratory Indicators\u003c/h3\u003e\n\u003cp\u003eAll laboratory indicators (CRP, Fc, ESR, Hb, Alb) were non-normally distributed (Shapiro-Wilk test, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and are therefore presented as median (IQR). Within-group comparisons were made using the Wilcoxon signed-rank test, and between-group comparisons using the Mann-Whitney U test.\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, baseline levels of all indicators were comparable between groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Within-group analysis revealed that the combination therapy group (A) experienced significant improvements from baseline in Hb (P\u0026thinsp;=\u0026thinsp;0.002), CRP (P\u0026thinsp;=\u0026thinsp;0.013), Alb (P\u0026thinsp;=\u0026thinsp;0.014), and ESR (P\u0026thinsp;=\u0026thinsp;0.001). In contrast, the monotherapy group (B) showed no significant within-group improvement for any laboratory indicator (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eBetween-group comparison at the end of follow-up showed that the combination therapy group had significantly lower levels of Fc (P\u0026thinsp;=\u0026thinsp;0.042) and ESR (P\u0026thinsp;=\u0026thinsp;0.013), and higher Alb (P\u0026thinsp;=\u0026thinsp;0.014) compared to the monotherapy group. No significant between-group differences were found in the final levels of CRP (P\u0026thinsp;=\u0026thinsp;0.400) or Hb (P\u0026thinsp;=\u0026thinsp;0.104).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Laboratory Indicators Between the Two Groups [Median (IQR)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndicator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBefore Treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAfter Treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChange (After-Before)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP (Within-Group)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP (Between-Groups, Post-Treatment)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.66 (1.00, 8.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.26 (0.50, 4.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.40 (0.08, 4.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.35 (2.00, 8.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.76(0.87, 5.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.80 (-1.66, 2.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e87.00 (23.50, 499.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38.00(23.00,100.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.00 (-18.00, 389.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e180.00(82.50,380.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e92.50(30.00,298.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e59.00 (-53.00, 231.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.00 (5.50, 20.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.00 (3.50, 6.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.00 (0.00, 15.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.50 (4.25, 24.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.00 (5.00, 16.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.50 (-3.00, 14.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e128.00(114.50,141.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e136.00(126.00,150.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.00 (-0.50, 19.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e127.00(115.00,138.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e131.00(113.25,145.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.50 (-11.75, 13.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.424\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42.40 (38.95, 44.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e45.20 (41.95, 46.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.80 (-1.05, 4.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42.90 (40.15, 46.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e42.25 (40.28, 44.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.20 (-3.15, 1.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNote\u003c/strong\u003e \u003cp\u003eData are presented as median (25th percentile, 75th percentile). The \u0026lsquo;Change\u0026rsquo; value represents the median (IQR) of the difference between post- and pre-treatment values. Within-group comparisons were performed using the Wilcoxon signed-rank test. Between-group comparisons of post-treatment values were performed using the Mann-Whitney U test. Bold indicates P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/p\u003e\n\u003ch3\u003e3. Efficacy Evaluation\u003c/h3\u003e\n\u003cp\u003e \u003cstrong\u003ePrimary Endpoint\u003c/strong\u003e \u003cp\u003eAt the end of follow-up, the endoscopic ulcer healing rate (Rutgeerts score i0-i1) was 82.76% (24/29) in Group A, significantly higher than the 25.00% (12/48) observed in Group B (χ\u0026sup2;=16.843, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Primary and Secondary Endpoints Between the Two Groups [n (%)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndicator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombined Treatment Group (Group A, n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBiologic Monotherapy Group (Group B, n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eχ\u0026sup2; Value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndoscopic Ulcer Healing Rate (i0-i1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24(82.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12(25.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical Remission Rate (No Complications)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26(89.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45(93.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.478\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.490\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP Normalization Rate (\u0026lt;\u0026thinsp;5 mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23(79.31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34(70.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.650\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.420\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSecondary Endpoints:\u003c/h3\u003e\n\u003cp\u003eClinical remission rate was 89.66% (26/29) in Group A and 93.75% (45/48) in Group B, with no statistically significant difference (χ\u0026sup2;=0.478, P\u0026thinsp;=\u0026thinsp;0.490).\u003c/p\u003e \u003cp\u003eCRP normalization rate was 79.31% (23/29) in Group A and 70.83% (34/48) in Group B; the difference was not statistically significant (χ\u0026sup2;=0.650, P\u0026thinsp;=\u0026thinsp;0.420).\u003c/p\u003e\n\u003ch3\u003e4. Survival Analysis\u003c/h3\u003e\n\u003cp\u003eKaplan-Meier analysis demonstrated significantly superior endoscopic remission-free survival in Group A compared to Group B (Log-rank P\u0026thinsp;=\u0026thinsp;0.007). The median time to endoscopic healing was 9.2 months in Group A, whereas it was not reached in Group B by the end of the study period. The cumulative healing rates at 6 months were 41.4% in Group A versus 16.7% in Group B, and at 12 months were 62.1% versus 29.2%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eKaplan-Meier curves show the cumulative probability of not achieving endoscopic ulcer healing over time. Endoscopic healing was defined as a Rutgeerts score of i0 or i1. Patients in the combination therapy group (black line, n\u0026thinsp;=\u0026thinsp;29) underwent endoscopic staple removal in addition to biologic therapy, while patients in the monotherapy group (blue line, n\u0026thinsp;=\u0026thinsp;48) received biologic therapy only. The difference between the groups was statistically significant by the log-rank test (P\u0026thinsp;=\u0026thinsp;0.007). The hazard ratio for ulcer healing, derived from a Cox regression analysis, was 2.15 (95% CI: 1.32\u0026ndash;3.51), indicating a significantly accelerated healing rate in the combination therapy group. The table beneath the plot displays the number of patients at risk in each group at sequential time points, with follow-up time in months.\u003c/p\u003e\n\u003ch3\u003e5.Representative Endoscopic Findings\u003c/h3\u003e\n\u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/strong\u003e \u003cp\u003eColonoscopic view of the anastomotic site in a patient with Crohn\u0026rsquo;s disease, 6 months after surgical resection of diseased bowel segments and subsequent ustekinumab therapy. The image demonstrates \u003cb\u003eRutgeerts score grade i3 anastomotic ulceration\u003c/b\u003e at the ileocolic anastomosis, with a visible stapler staple adjacent to the ulcer. The staple was removed endoscopically during this follow-up examination.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFigure 3\u003c/strong\u003e \u003cp\u003eColonoscopic view of the same anastomotic site 9 months after staple removal (15 months post-surgical resection and ustekinumab initiation). The anastomotic ulceration has resolved substantially, with only mild \u003cb\u003emucosal hyperemia\u003c/b\u003e noted at the anastomotic line.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003c/strong\u003e \u003cp\u003eColonoscopic view of the ileocolic anastomosis in a patient with Crohn\u0026rsquo;s disease, 6 months after surgical bowel resection and maintenance infliximab therapy. The image demonstrates a \u003cb\u003elarge anastomotic ulceration (Rutgeerts score i4)\u003c/b\u003e accompanied by anastomotic stenosis, with a visible surgical staple adjacent to the lesion. The staple was removed endoscopically during this follow-up evaluation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFigure 5\u003c/strong\u003e \u003cp\u003eColonoscopic view of the same anastomotic site at the time of staple removal (concurrent with Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e), confirming the extent of the grade i4 ulceration and stenosis.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFigure 6\u003c/strong\u003e \u003cp\u003eColonoscopic view of the anastomotic site 15 months after staple removal (21 months post-surgical resection and infliximab initiation). The large anastomotic ulceration has resolved completely, with only mild \u003cb\u003emucosal hyperemia\u003c/b\u003e present at the anastomotic line.\u003c/p\u003e \u003c/p\u003e\n\u003ch3\u003e6. Safety Assessment\u003c/h3\u003e\n\u003cp\u003eAll endoscopic staple removal procedures were successfully completed without major complications such as perforation or significant bleeding. Two patients (6.9%) in Group A experienced transient mild abdominal pain or melena that resolved spontaneously without intervention. The incidence of biologic therapy-related adverse events was low and comparable between groups (3.4% vs. 6.3%, P\u0026thinsp;=\u0026thinsp;0.589).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective cohort study, endoscopic staple removal combined with biologic therapy was found to significantly improve endoscopic outcomes in CD patients with PAUs compared to biologic therapy alone. The combination approach yielded substantially higher rates of mucosal healing and a markedly shorter time to endoscopic remission.\u003c/p\u003e \u003cp\u003eAnalysis of serial laboratory indicators provided compelling objective evidence reinforcing the therapeutic advantage of the combined strategy. A key distinction emerged from the within-group analysis: statistically significant improvements from baseline across multiple parameters\u0026mdash;including Hb, CRP, Alb, and ESR\u0026mdash;were observed exclusively in the combination therapy group. This pattern suggests that endoscopic staple removal may potentiate or accelerate the systemic anti-inflammatory and reparative effects mediated by biologic agents. Moreover, direct between-group comparison at the endpoint revealed that the combination therapy group achieved significantly more favorable levels of Fc, ESR, and Alb. The consistent and significant improvement in serum albumin, a marker of nutritional status and chronic inflammatory burden, implies that benefits of the combined strategy may extend beyond local mucosal healing to ameliorate systemic sequelae of CD [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003ePotential Mechanisms\u003c/h3\u003e\n\u003cp\u003eThese findings lend strong support to the pathophysiological hypothesis that retained surgical staples act as foreign bodies, perpetuating local inflammation and impairing tissue repair through mechanisms such as persistent mechanical irritation, microcirculatory disturbance, and activation of innate immune pathways [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The observation that significant reductions in systemic (CRP, ESR) and gut-specific (fecal calprotectin) inflammatory markers occurred predominantly within the combination group provides tangible laboratory evidence for this mechanistic premise. The survival analysis further underscores the clinical impact of this intervention. Achieving early endoscopic remission is of paramount importance, as it has been consistently linked to superior long-term outcomes in CD, including a reduced risk of clinical relapse and re-operation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe decision for endoscopic intervention was based on endoscopist preference rather than randomization, introducing a potential for selection bias. However, the balanced baseline characteristics between the two groups strengthen the validity of the comparative analysis.\u003c/p\u003e \u003cp\u003eThe dissociation between significant improvements in endoscopic/laboratory endpoints and the non-significant difference in clinical remission rates is noteworthy. This phenomenon has been recognized in postoperative CD management, where symptomatic response may lag behind objective mucosal healing [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, our definition of clinical remission, while clinically practical, may be less sensitive than validated disease activity indices for detecting subtle symptomatic changes. This underscores the paramount importance of endoscopic evaluation as the gold standard for assessing treatment efficacy in the postoperative setting.\u003c/p\u003e \u003cp\u003eThe safety profile of endoscopic staple removal in this cohort was excellent, aligning with prior reports establishing its technical feasibility and safety when performed by experienced endoscopists [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eSeveral limitations of this study must be acknowledged. First, the retrospective, non-randomized design carries an inherent risk of selection and confounding bias. Second, although the sample size was sufficient to detect a significant difference in the primary endpoint, the relatively small number of patients in the combination therapy group may have limited the statistical power for some secondary outcomes. The use of a non-validated clinical endpoint and the lack of central, blinded review for endoscopic scores are additional constraints. Future prospective, randomized controlled trials with standardized protocols, central endoscopic reading, and incorporation of patient-reported outcomes are warranted to confirm these findings and precisely define the role of endoscopic staple removal in the postoperative management algorithm for CD.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides evidence that endoscopic staple removal combined with biologic therapy is significantly more effective than biologic therapy alone in achieving endoscopic mucosal healing for PAUs in CD patients, with a comparable safety profile. The combination approach resulted in higher healing rates, accelerated time to endoscopic remission, and was associated with significant improvements in several key laboratory indicators which were not observed with monotherapy. These findings support the concept that foreign body removal may enhance the efficacy of biological therapy in the postoperative setting. While confirmation through prospective trials is warranted, endoscopic staple removal represents a promising adjunctive strategy for managing postoperative recurrence in CD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions: Wei Cheng: Conceptualization, Methodology, Formal Analysis, Investigation, Data Curation, Writing \u0026ndash; Original Draft, Visualization. Zhao Runpeng: Conceptualization, Methodology, Investigation, Data Curation, Writing \u0026ndash; Review \u0026amp; Editing. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003eFunding: Not applicable.\u003c/p\u003e\n\u003cp\u003eData Availability Statement: The datasets generated during and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eEthics Approval and Consent to Participate: This study was approved by the Institutional Review Board of Nanjing Second Hospital. All procedures performed were in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments. The need for informed consent was waived by the Institutional Review Board of Nanjing Second Hospital due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003eConsent for Publication: Not applicable.\u003c/p\u003e\n\u003cp\u003eConflict of Interest: The authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRivi\u0026egrave;re P, Vermeire S, Irles-Depe M, et al. Rates of postoperative recurrence of Crohn's disease and effects of immunosuppressive and biologic therapies. 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Nat Rev Gastroenterol Hepatol. 2016;13(10):567\u0026ndash;79. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nrgastro.2016.128\u003c/span\u003e\u003cspan address=\"10.1038/nrgastro.2016.128\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Crohn's Disease, Anastomotic Ulcer, Endoscopic Staple Removal, Biologics, Mucosal Healing, Retrospective Study","lastPublishedDoi":"10.21203/rs.3.rs-8485301/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8485301/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aimed to evaluate the efficacy and safety of endoscopic staple removal combined with biologic therapy versus biologic therapy alone for postoperative anastomotic ulcers (PAUs) in Crohn's disease (CD).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective analysis was conducted on 77 CD patients diagnosed with PAUs (Rutgeerts score\u0026thinsp;\u0026ge;\u0026thinsp;i2) following ileocolonic resection who received biologic therapy at Nanjing Second Hospital between January 2021 and August 2025. Based on the administration of endoscopic staple removal, patients were categorized into a combination therapy group (Group A, n\u0026thinsp;=\u0026thinsp;29) and a biologic monotherapy group (Group B, n\u0026thinsp;=\u0026thinsp;48). The primary endpoint was the endoscopic ulcer healing rate (Rutgeerts score i0-i1) at final follow-up. Secondary endpoints included clinical symptom remission rate, normalization rate of serum CRP (\u0026lt;\u0026thinsp;5 mg/L), endoscopic remission-free survival, and adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBaseline characteristics were comparable between groups. The endoscopic healing rate was significantly higher in Group A than in Group B (82.76% vs. 25.00%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Analysis of laboratory indicators, presented as median (IQR), demonstrated that Group A achieved significantly greater improvements in Alb (P\u0026thinsp;=\u0026thinsp;0.014) and ESR (P\u0026thinsp;=\u0026thinsp;0.013) at follow-up, whereas no significant inter-group differences were observed in the magnitude of change for CRP, Fc, or Hb. Survival analysis revealed a significantly shorter median time to endoscopic healing in Group A (9.2 months vs. not reached, Log-rank P\u0026thinsp;=\u0026thinsp;0.007). Adverse event rates were comparable.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEndoscopic staple removal combined with biologic therapy is more effective than biologic therapy alone in promoting endoscopic mucosal healing for PAUs after CD surgery, with a comparable safety profile.\u003c/p\u003e","manuscriptTitle":"Endoscopic Staple Removal Combined with Biologic Therapy Enhances Postoperative Anastomotic Ulcer Healing in Crohn’s Disease: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 16:46:49","doi":"10.21203/rs.3.rs-8485301/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-24T12:52:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180190120919707027470184293003369259562","date":"2026-02-12T14:29:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"177528589491635466446624602231203178608","date":"2026-02-12T14:17:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-05T10:11:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-04T09:42:04+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-12T05:49:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-10T01:58:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Gastroenterology","date":"2026-01-10T01:53:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6f3ee45f-4b8d-429a-950a-755be88a8725","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:46:49+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-09 16:46:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8485301","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8485301","identity":"rs-8485301","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}