Crohn’s disease complicated with intestinal fistulas: Exclusive enteral nutrition or Biologics?

Crohn’s disease complicated with intestinal fistulas: Exclusive enteral nutrition or Biologics? | 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 Crohn’s disease complicated with intestinal fistulas: Exclusive enteral nutrition or Biologics? Xiaoxia Deng, Zhaopeng Huang, Jiawei Zhan, Yanhui Wu, Na Diao, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7418997/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Approximately 16% of adult patients with Crohn's disease (CD) are complicated with intestinal fistulas. Both exclusive enteral nutrition (EEN) and biologics have shown potential efficacy. We aimed to compare the efficacy of EEN and biologics in adult CD with intestinal fistulas and to explore the preferred choice for these patients. Methods This single-center, retrospective study involved adult CD patients with active intestinal fistulas who received EEN or biologics induction therapy from January 2014 to May 2024. Exclusion criteria included concurrent abdominal abscesses or symptomatic intestinal obstruction. The primary endpoint was clinical remission. The secondary outcomes encompassed clinical response, radiological response, transmural healing, fistula healing, endoscopic response, endoscopic remission, C-reactive protein (CRP) normalization, and surgery. Results A total of 108 patients (47 biologics and 61 EEN) were enrolled. At baseline, the EEN group exhibited more complex intestinal fistulas, higher inflammatory burden, and poorer nutritional status compared to the biologics group. The EEN group showed higher rates of fistula healing (23% vs. 6.4%, P = 0.019), radiological response (93.4% vs. 68.1%, P = 0.001), CRP normalization (73.8% vs. 55.3%, P = 0.045), and surgery (16.4% vs. 2.1%, P = 0.040). Conclusions EEN and biologics are clinically effective treatments for adult CD patients with intestinal fistulas. Biologics are preferred for patients without tolerance of EEN. EEN is preferred for patients with complex intestinal fistulas, severe activity, and malnutrition. Exclusive enteral nutrition Biologics Active Crohn’s disease Intestinal fistulas Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract that affects the entire intestinal wall. 1 A 25-year follow-up study suggested that 29.4% of CD patients progressed from inflammatory behavior to penetrating behavior over 10 years. 2 Intestinal fistula refers to a pathological connection between the intestine and either the inner or outer epithelial surface, occurring in approximately 16% of adult patients with CD. 3 A population-based cohort study has indicated a 33% risk of developing a fistula after 10 years, rising to 50% after 20 years. 4 The International Organization for the Study of Inflammatory Bowel Disease (IOIBD) has proposed that fistula was the second most important determinant of overall disease severity in CD. 5 The presence of intestinal fistulas predicts aggressive disease, reduced quality of life, and early surgery, and its management requires multidisciplinary cooperation, with medical therapy as the cornerstone. 6 For CD patients with a penetrating phenotype, there are standard strategies for abdominal abscesses. 7 However, the recommended standard care is lacking in patients with intestinal fistulas without abscesses. Biologic therapies have been the mainstay of medical treatment of fistulizing CD, but the patients enrolled in the study were mostly those with perianal fistulas. 8 The ACCENT trial, the first and only randomized clinical trial to evaluate biologics in fistulizing CD, included only 38 patients with intestinal fistulas. 9 CD patients with intestinal fistulas always presented more severe activity and malnutrition. 10 Exclusive enteral nutrition (EEN) is a nutritional approach that provides patients with 100% of their nutritional requirements by oral or nasal feeding. 11 EEN presented obvious benefits in managing CD, as it effectively induces clinical remission, improves nutritional status, promotes mucosal healing, and reduces levels of proinflammatory cytokines, with minimal adverse effects. 12 A previous study in India suggested EEN effectively induced complete healing in active CD patients complicated with enteroenteric fistulae, while the sample is relatively small. 13 In our previous studies, EEN is effective in patients with penetrating complications. 14 However, EEN is less tolerant in adult patients than in paediatric patients. Choosing the right strategy for the right patient is of great clinical significance. We aimed to compare the efficacy and prognosis between EEN and biologics in adult CD with intestinal fistulas, and to explore the preferred choice of treatment strategy for these patients in clinical practice. Methods Study population This was a single-center, retrospective, observational cohort study that enrolled CD patients from January 2014 to May 2024. The study was approved by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (E2024065). All procedures were performed under the principles of the Declaration of Helsinki. The inclusion criteria were: (1)age ≥ 18 years; (2)diagnosed as CD based on clinical, endoscopic, radiological, and pathological manifestations; 15 (3) intestinal fistulas confirmed by radiological imaging[e.g., computed tomography enterography (CTE), magnetic resonance enterography (MRE), bowel ultrasound]; 16 (4) active stage; (5) received EEN therapy for 12 weeks or standard biological [e.g., infliximab (IFX) or ustekinumab(UST) ]induction therapy. The following patients were excluded: (1) those with incomplete clinical data; (2) patients in pregnancy or lactation; (3) those requiring emergency surgery; (4) those combined with abdominal abscess or symptomatic intestinal obstruction. Investigated drugs Both UST and IFX were given at standard-label doses. Intravenous infusions of IFX at a dosage of 5 mg/kg at 0, 2, and 6 weeks were prescribed for inducing remission. UST was initiated with a weight-based intravenous infusion (260 mg ≤ 55 kg, 390 mg between 55 kg and 85 kg, 520 mg > 85 kg) in the induction period, and followed by subcutaneous UST (90 mg every 8 weeks) afterward. In the EEN group, patients received enteral nutrition with an amino acid, peptide, or protein-type formula by nasogastric feeding or orally for 12 weeks. Daily calorie intake was 25–30 kcal/kg/d. 17 No combination therapies, including steroids and immunosuppressants, were used in these patients. Data collection The clinical characteristics at baseline and after therapy were collected from the electronic medical records. Clinical evaluations were performed at weeks 12 to 14 for EEN and IFX, and at weeks 16–24 for UST. The following data were collected, including sex, age, body mass index (BMI), disease characteristics (e.g., disease location, disease behavior, perianal lesions), upper gastrointestinal involvement, previous surgery history related to CD (including perianal and intestinal surgery), previous medication history, disease activity scores, inflammatory index [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)],nutrition-related index [(hemoglobin (HGB), albumin (ALB)], endoscopic manifestations, ultrasound manifestations, CT or MR manifestations. Definition Disease phenotype was classified according to the Montreal classification. 18 Disease activity was assessed using the Harvey-Bradshaw Index (HBI). HBI ≤ 4 was defined as a remission period. HBI ranging from 5–7, 8–16, and > 16 were defined as mild, moderate, and severe activity. Clinical response was defined by a decrease ≥ 3 in HBI score. 19 Endoscopic response was defined as ≥ 50% decrease of SES-CD score, with SES-CD score ≤ 2 was classified as endoscopic remission 20 . Radiographic assessment through CTE, MRE, or bowel ultrasound. Radiographic response referred to improvement in intestinal wall thickness, mesenteric inflammatory fat, intestinal wall blood flow, and intestinal wall enhancement signal from baseline. 19 Radiographic assessment includes active intestinal inflammation (increased bowel wall thickening, presence of ulceration, edema, or increased contrast enhancement), pericentric inflammation (comb sign, enlarged lymph nodes, fat creeping), and CD-related complications (stricture, sinus tract/fistula, abscess or inflammatory mass) for each intestinal segment (jejunum, ileum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum). Given the intra-segment heterogeneity, we measured the most affected section. Transmural healing was defined as no sign of active intestinal inflammation, absence of peri-enteric inflammation, and no CD-related complications 21 . Simple fistula was classified as a single fistulous tract, and complex fistula was defined as 2 or more fistula tracts, 22 – 24 and fistula healing refers to the disappearance of fistulas observed through various imaging techniques. 23 CRP normalization refers to a CRP level < 5 mg/L. 25 Surgical treatment included surgeries for penetrating lesions such as intestinal resection, fistula excision, fistula repair, and stomy. 26 , 27 Outcomes The primary outcome was clinical remission. The secondary outcomes were clinical response, fistula healing, radiological response, transmural healing, endoscopic response, endoscopic remission, CRP normalization, and surgery. Statistical analysis All data were analyzed and processed using SPSS 25.0 (SPSS, Chicago, IL). The Kolmogorov-Smirnov test was used to determine whether the continuous variables were normally distributed. Continuous variables with a normal distribution were represented by the mean and standard deviation (± SD), while non-normal continuous variables were represented by the median and interquartile range (IQR). Categorical variables were presented as numbers and percentages (n, %). Continuous variables were compared using the t-test (normal distribution) or the Wilcoxon test (non-normal distribution). Categorical variables were measured by the Chi-square test or Fisher's exact probability method. Univariate and multivariate logistic regression analyses were used to identify predictors affecting clinical remission. Variables with P < 0.2 in the univariate analysis were included in the multivariate analysis. All P- values were two-sided, and P < 0.05 was considered statistically significant. Results Patient characteristics at baseline A total of 108 patients were included in the study, including 47 cases treated with biologics (27 UST and 20 IFX) and 61 cases with EEN (Fig. 1 ). There were no significant differences between the two groups regarding sex, disease duration, and disease characteristics (e.g., age at diagnosis, disease location, disease behavior, perianal lesions, upper gastrointestinal involvement, and previous surgery history). The proportion of previous medication history in the biologics group was significantly higher than that in the EEN group (78.7% vs. 45.9%, P = 0.001). There were significant differences in the classification of fistula tract ( P = 0.001) and type of fistulas ( P = 0.019) between the two groups (Table 1 ). In addition, the patients in the EEN group showed more moderate-severe activity ( P = 0.012), higher inflammatory burden (including ESR and CRP), and poorer nutritional status (including BMI, ALB, and HGB) than those in the biologics group (All P- values < 0.05) (Fig. 2 and Fig. 3 ). Table 1 The clinical characteristics of CD patients at baseline Characteristics Biologics EEN P (n = 47) (n = 61) Male, n (%) 33 (70.2) 40 (65.6) 0.610 Disease duration (months, median [IQR]) 57.0 (25.0, 98.0) 52.0 (13.0, 97.0) 0.493 Age at diagnosis (years, median [IQR]) 26.0 (20.0,34.0) 30.0 (25.5, 35.0) 0.055 Montreal classification, n (%) Age at diagnosis 0.508 0–16 years old (A1) 3 (6.4) 1 (1.6) 17–40 years old (A2) 37 (78.7) 51 (83.6) > 40 years old (A3) 7 (14.9) 9 (14.8) Disease location Ileal (L1) 2 (4.3) 7 (11.5) 0.320 Ileocolonic (L3) 45 (95.7) 54 (88.5) Upper gastrointestinal involvement 21 (44.7) 26 (42.6) 0.831 Perianal lesions 38 (80.9) 44 (72.1) 0.293 Previous medication history, n (%) 37 (78.7) 28 (45.9) 0.001 Corticosteroids, n (%) 17 (36.2) 16 (26.2) 0.266 EEN, n (%) 28 (59.6) 4 (6.6) < 0.001 Immunomodulators, n (%) 25 (53.2) 17 (27.9) 0.007 Biologics, n (%) 19 (40.4) 7 (11.5) < 0.001 Previous surgery history, n (%) 25 (53.2) 30 (49.2) 0.679 Previous perianal surgery, n (%) 16 (34.0) 18 (29.5) 0.615 Previous intestinal surgery, n (%) 13 (27.7) 14 (23.0) 0.575 Classification of fistula tract, n (%) 0.001 Simple fistula 46 (97.9) 46 (75.4) Complex fistula 1 (2.1) 15 (24.6) Types of fistulas, n/N (%) 0.019 Enteric fistula 45/48 (93.8) 56/76 (73.7) Enterocutaneous fistula 2/48 (4.2) 11/76 (14.5) Vesical fistula 1/48 (2.1) 9/76 (11.8) HBI scores at baseline (median [IQR]) 6.0 (5.0, 7.0) 8.0 (6.0, 9.0) 0.001 Disease activity, n (%) 0.002 Mild activity 36 (76.6) 28 (45.9) Moderate activity 11 (23.4) 32 (52.5) Severe activity 0 (0.0) 1 (1.6) Values are presented as numbers (%). EEN, exclusive enteral nutrition; IQR, interquartile range; HBI, Harvey-Bradshaw Index. Outcome measures Clinical remission and clinical response The rate of clinical remission was 55.3% (26/47) in patients with biologics, and 41% (25/61) in patients with EEN. No differences were found between the two groups ( P = 0.139) (Fig. 4 a). The baseline HBI (OR 0.75, 95% CI, 0.60–0.93, P = 0.010) was negatively correlated with clinical remission (Supplementary Table 1). A total of 39 patients in the EEN group (63.9%) and 29 patients in the biologics group (61.7%) achieved clinical response, with no significant differences between the two groups ( P = 0.812) (Fig. 4 a). Fistula healing, transmural healing and radiological response A total of 17 CD patients (15.7%) achieved fistula healing. The rate of fistula healing was significantly higher in the EEN group than in the biologics group (23.0% vs. 6.4%, P = 0.019) (Fig. 4 b). Additionally, the rate of transmural healing was comparable between EEN and biologics group (13.1% vs. 6.4%, P = 0.409) (Fig. 4 b). A total of 89 CD patients (82.4%) achieved radiological response, including 32 cases in biologics group (68.1%) and 57 cases in EEN group (93.4%). EEN was superior to biologics in inducing radiological response ( P = 0.001) (Fig. 4 c). Endoscopic response and endoscopic remission Seventy-three patients (18 UST, 17 IFX, and 38 EEN) completed endoscopic evaluation both at baseline and after treatment. The rate of endoscopic response was comparable between EEN and biologics group (76.3% vs. 62.9%, P = 0.211) (Fig. 4 d). There were 21 patients in EEN group (55.3%) and 14 patients in biologics group (40%) who achieved endoscopic remission, with no significant differences between the two groups ( P = 0.192) (Fig. 4 d). CRP normalization The rate of CRP normalization was significantly higher in EEN group than biologics group (73.8% vs. 55.3%, P = 0.045) (Fig. 4 c). Surgery There were 10 patients in EEN group (16.4%) and 1 patient in biologics group (2.1%) underwent surgery, with significant differences between the two groups ( P = 0.040). Among patients who underwent surgery in EEN, 70% (7/10) were complex intestinal fistulas. Nine (90%) patients underwent surgery because of intestinal fistula, and two (20%) patients underwent surgery because of intestinal obstruction. Specifically, one patient showed both intestinal fistula and intestinal obstruction simultaneously. One patient received surgery in UST because of complex intestinal fistulas. Changes in inflammatory burden and nutritional status After treatment, the EEN group showed lower CRP level ( P = 0.011) than that in biologics group, Other inflammatory and nutritional indexes were comparable between the two groups (Fig. 2 and Fig. 3 ). Subgroup analysis In terms of baseline characteristics, the differences in baseline characteristics between the EEN group and the UST group, as well as between the EEN group and the IFX group, were similar to those between the EEN group and the biologics group. (Supplementary Table 2 and Supplementary Table 3). Compared to the UST group, the EEN group showed higher inflammatory burden (including ESR and CRP) and poorer nutritional status (including BMI, ALB, and HGB) at baseline, while lower CRP after treatment (All P- values < 0.05) (Supplementary Fig. 1 and Supplementary Fig. 2). Additionally, the EEN group showed lower BMI ( P = 0.003) at baseline, while higher ALB ( P = 0.040) after treatment. (Supplementary Fig. 1 and Supplementary Fig. 2). Notably, EEN was superior to UST in inducing radiological response ( P = 0.001), but other clinical, endoscopic, and radiological outcomes between the EEN group and UST group, as well as between the EEN group and the IFX group were comparable. (Supplementary Table 4, Supplementary Table 5, and Supplementary Fig. 3). Discussion In the present study, we focused on a specific population lacking recommended standard care, CD patients complicated with intestinal fistulas but not abscesses. The previous study recommended biologics as a non-surgical treatment in these patients. 28 However, high-grade evidence supporting this approach remains inadequate. EEN is also effective in patients with complications, 13 , 14 but is difficult to follow. In the present study, we found that both EEN and biologics were effective in these patients. For patients with complex intestinal fistulas, more severe activity and malnutrition, EEN may have an advantage. The studies of intestinal penetrating CD were rare, for the baseline characteristics were complex in these patients, such as types, number, location and complicated situations of fistulas. In our study, we excluded patients with abscess or symptomatic intestinal obstruction. In these patients, non-surgical treatment is the first choice. To find which strategy is better, we compared two commonly used strategies. The baseline characteristics were significantly different in the two groups, although we tried some methods, such as Propensity Score Matching. It is consistent with the clinical setting after shared decision-making. This clinical decision-making tendency may be related to the efficacy of EEN in improving nutritional status and reducing inflammatory burden. Patients with more severe activity, more complex intestinal fistulas, heavier inflammatory burden, and worse nutritional status tend to accept EEN. Patients treated with EEN showed similar clinical, endoscopic, and radiological efficacy despite more severe disease, compared to patients using biologics. Additionally, EEN showed higher rates of fistula healing and radiological response compared to biological therapy. It is worth noting that the inflammatory burden and nutritional status after treatment were comparable between the biologics group and the EEN group. Our results suggest that both EEN and biologics are effective in CD patients with intestinal fistulas. Given the differences in baseline characteristics, EEN has more advantages in patients with heavier inflammatory burden, more severe disease activity, complex intestinal fistulas, and malnutrition. A retrospective multicenter cohort study included 760 fistulizing CD receiving biologic therapy, including 673 anti-tumor necrosis factors, 69 UST, and 18 vedolizumab, showed that 24% of patients achieved fistula closure 29 . In CD adults with complications, 75% of patients with abdominal fistulas achieved fistula closure after 12 weeks of EEN treatment. 14 In the biologics group, all patients who achieved fistula healing were simple fistulas. Similarly, previous studies have reported that in patients with CD complicated with enterocutaneous fistula treated with IFX, the failure of fistula healing is associated with complex fistulas. 22 While in patients with EEN, two patients with complex fistulas also achieved fistula healing. Nevertheless, the surgical rate in the EEN group was higher than that in the biologics group. This condition may be related to the higher proportion of patients with complex intestinal fistulas and more severe disease activity in the EEN group. A multicenter retrospective cohort study in France reported that complex intestinal fistulas are associated with surgery. 24 We observed that complex intestinal fistulas are the main cause of surgery, similar to previous studies. 19 , 24 The data from our center indicated that both EEN and biologics can promote fistula healing, but they cannot completely avoid surgery. For complex fistulas, EEN may be a better choice. In a Danish multicenter cohort of adult patients treated with anti-tumor necrosis factors, higher baseline HBI was less likely to achieve clinical remission 30 . Our result also showed that a higher baseline HBI was associated with lower clinical remission in patients with complex intestinal fistulas. This study has several limitations. Firstly, due to the respective nature, some baseline characteristics were different in the two groups, which may cause bias. Secondly, the sample size is relatively small, head-to-head comparative studies with large sample sizes are needed to prove our findings in the future. Conclusions In conclusion, EEN and biologics are clinically effective treatments for adult CD with intestinal fistulas, presenting similar clinical remission rate, and they both can achieve endoscopic and radiological improvement. However, the intolerance of EEN limits its application in some patients, and biologics are preferred for these patients in clinical practice. For patients with complex intestinal fistulas, more severe disease, and malnutrition, EEN may be a good choice. Abbreviations CD Crohn's disease IOIBD International Organization for the Study of Inflammatory Bowel Disease EEN Exclusive enteral nutrition CTE Computed tomography enterography MRE Magnetic resonance enterography IFX Infliximab UST Ustekinumab BMI body mass index CRP C-reactive protein ESR Erythrocyte sedimentation rate HGB Hemoglobin ALB Albumin SD Standard deviation IQR Interquartile range HBI Harvey-Bradshaw Index (HBI) CI Confidence interval OR Odds ratio Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (E2024065). All procedures were performed under the principles of the Declaration of Helsinki. Written informed consent was waived due to the retrospective study design. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests. Funding The study was funded by the National Key R&D Program of China (2023YFC2507300), National Natural Science Foundation of China (No.82470570), and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004). Author contributions CK and TJ contributed to the study design. YQF and HZC were responsible for patient recruitment. DXX, HZP, JWZ, WYH, and DN performed data collection. DXX, HZP, and JWZ conducted the data analysis. GQ, LM, and YHS provided supervision throughout the development of the study. GX administered the project. CK and YQF reviewed and revised the manuscript. All authors approved the final version of the manuscript including the authorship list. All authors have read and approved the final manuscript. Acknowledgments Not applicable. References Singh S, Proctor D, Scott FI, Falck-Ytter Y, Feuerstein JD. AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing. Crohn's Disease Gastroenterol. 2021;160(7):2512–e25562519. Louis E, Collard A, Oger AF, et al. Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course. disease Gut. 2001;49(6):777–82. Hirten RP, Shah S, Sachar DB, Colombel JF. The Management of Intestinal Penetrating Crohn's Disease. Inflamm Bowel Dis. 2018;24(4):752–65. Schwartz DA, Loftus EV, Tremaine WJ, et al. The natural history of fistulizing Crohn's disease in Olmsted County. Minn Gastroenterol. 2002;122(4):875–80. Siegel CA, Whitman CB, Spiegel BMR, et al. Development of an index to define overall disease severity in. IBD Gut. 2018;67(2):244–54. Levy C, Tremaine WJ. Management of internal fistulas in Crohn's disease. Inflamm Bowel Dis. 2002;8(2):106–11. Casas Deza D, Polo Cuadro C, de Francisco R, et al. Initial Management of Intra-abdominal Abscesses and Preventive Strategies for Abscess Recurrence in Penetrating Crohn's Disease: A National, Multicentre Study Based on ENEIDA Registry. J Crohns Colitis. 2024;18(4):578–88. Lee MJ, Parker CE, Taylor SR, et al. Efficacy of Medical Therapies for Fistulizing Crohn's Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(12):1879–92. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease.N Engl. J Med. 2004;350(9):876–85. Wu Y, He Y, Chen F, et al. [Nutritional risk screening in patients with Crohn's disease]. Zhonghua Yi Xue Za Zhi. 2016;96(6):442–6. Fansiwala K, Shah ND, McNulty KA, Kwaan MR, Limketkai BN. Use of oral diet and nutrition support in management of stricturing and fistulizing Crohn's disease. Nutr Clin Pract. 2023;38(6):1282–95. Hartman C, Eliakim R, Shamir R. Nutritional status and nutritional therapy in inflammatory bowel diseases. World J Gastroenterol. 2009;15(21):2570–8. Sood A, Singh A, Sudhakar R, et al. Exclusive enteral nutrition for induction of remission in anti-tumor necrosis factor refractory adult Crohn's disease: the Indian experience. Intest Res. 2020;18(2):184–91. Yang Q, Gao X, Chen H, et al. Efficacy of exclusive enteral nutrition in complicated Crohn's disease. Scand J Gastroenterol. 2017;52(9):995–1001. M'Koma AE. Inflammatory Bowel Disease: Clinical Diagnosis and Surgical Treatment-Overview.Medicina. (Kaunas) 2022;58(5). Schmidt S, Chevallier P, Bessoud B, et al. Diagnostic performance of MRI for detection of intestinal fistulas in patients with complicated inflammatory bowel conditions. Eur Radiol. 2007;17(11):2957–63. Guo Z, Wu R, Zhu W, et al. Effect of exclusive enteral nutrition on health-related quality of life for adults with active Crohn's disease. Nutr Clin Pract. 2013;28(4):499–505. Satsangi J, Silverberg MS, Vermeire S, Colombel JF, Gut. 2006;55(6):749–53. Kotze PG, Ma C, Almutairdi A, et al. Real-world clinical, endoscopic and radiographic efficacy of vedolizumab for the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2018;48(6):626–37. Daperno M, D'Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505–12. Lafeuille P, Hordonneau C, Vignette J, et al. Transmural healing and MRI healing are associated with lower risk of bowel damage progression than endoscopic mucosal healing in Crohn’s disease. Aliment Pharmacol Ther. 2020;53(5):577–86. Amiot A, Setakhr V, Seksik P, et al. Long-term outcome of enterocutaneous fistula in patients with Crohn's disease treated with anti-TNF therapy: a cohort study from the GETAID. Am J Gastroenterol. 2014;109(9):1443–9. Bouguen G, Huguet A, Amiot A, et al. Efficacy and Safety of Tumor Necrosis Factor Antagonists in Treatment of Internal Fistulizing Crohn's Disease. Clin Gastroenterol Hepatol. 2020;18(3):628–36. Ma Y, Zhang R, Liu W, et al. Prognostic factors for the efficacy of infliximab in patients with luminal fistulizing Crohn's disease. BMC Gastroenterol. 2023;23(1):57. Wilkens R, Novak KL, Maaser C, Panaccione R, Kucharzik T. Relevance of monitoring transmural disease activity in patients with Crohn's disease: current status and future perspectives. Th Adv Gastroenterol. 2021;14:17562848211006672. Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing. Crohn's disease Gastroenterol. 2005;128(4):862–9. Jones DW, Finlayson SRG. Trends in Surgery for Crohn's Disease in the Era of Infliximab. Ann Surg. 2010;252(2):307–12. Tjandra D, Garg M, Behrenbruch C, et al. Review article: investigation and management of internal fistulae in Crohn's disease. Aliment Pharmacol Ther. 2021;53(10):1064–79. Barreiro-de Acosta M, Fernández-Clotet A, Mesonero F, et al. Long-Term Outcomes of Biological Therapy in Crohn's Disease Complicated With Internal Fistulizing Disease: BIOSCOPE Study From GETECCU.Am. J Gastroenterol. 2023;118(6):1036–46. Zhao M, Larsen L, Dige A et al. Clinical outcomes after first-line anti-TNF treatment of patients with inflammatory bowel disease - a prospective multicenter cohort study. J Crohns Colitis 2025;19(5). Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable.docx SupplementaryFigure1.tif SupplementaryFigure2.tif SupplementaryFigure3.tif Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7418997","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507383734,"identity":"c3784a18-2218-446c-9ed4-0ea0da2f2c30","order_by":0,"name":"Xiaoxia Deng","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoxia","middleName":"","lastName":"Deng","suffix":""},{"id":507383737,"identity":"0cee3b56-8455-45c8-ac37-344a7e943b05","order_by":1,"name":"Zhaopeng Huang","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Zhaopeng","middleName":"","lastName":"Huang","suffix":""},{"id":507383738,"identity":"b711ed3f-089f-45d9-a6bd-762ba6674010","order_by":2,"name":"Jiawei Zhan","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Jiawei","middleName":"","lastName":"Zhan","suffix":""},{"id":507383739,"identity":"ab379436-7ca2-47be-9e3c-fcbded6a060a","order_by":3,"name":"Yanhui Wu","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yanhui","middleName":"","lastName":"Wu","suffix":""},{"id":507383744,"identity":"ee0878ff-8745-4d58-a8fc-4f9d1586b5c6","order_by":4,"name":"Na Diao","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Diao","suffix":""},{"id":507383745,"identity":"f2bab874-4d3b-4504-9375-e066286f0d4a","order_by":5,"name":"Jian Tang","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"Tang","suffix":""},{"id":507383746,"identity":"e93c1fab-3d57-42df-adf6-cd70cc7fd04b","order_by":6,"name":"Zicheng Huang","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Zicheng","middleName":"","lastName":"Huang","suffix":""},{"id":507383747,"identity":"26c006bb-0d03-4201-b57f-30daf04bef14","order_by":7,"name":"Qin Guo","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Guo","suffix":""},{"id":507383748,"identity":"077a74a6-c527-456b-a742-ab8145ceedd0","order_by":8,"name":"Miao Li","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Miao","middleName":"","lastName":"Li","suffix":""},{"id":507383749,"identity":"f0f1a599-a287-40a4-82ac-3bbadd8ceb35","order_by":9,"name":"Hongsheng Yang","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Hongsheng","middleName":"","lastName":"Yang","suffix":""},{"id":507383750,"identity":"f87ada6b-3ccb-465d-9285-243503d4c8dc","order_by":10,"name":"Xiang Gao","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Gao","suffix":""},{"id":507383752,"identity":"2ede6132-bc7c-42f0-a250-156373707577","order_by":11,"name":"Qingfan Yang","email":"","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Qingfan","middleName":"","lastName":"Yang","suffix":""},{"id":507383753,"identity":"2b073213-0426-40b5-a1a1-32705b212c07","order_by":12,"name":"Kang Chao","email":"data:image/png;base64,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","orcid":"","institution":"Sixth Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Kang","middleName":"","lastName":"Chao","suffix":""}],"badges":[],"createdAt":"2025-08-20 15:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7418997/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7418997/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90380702,"identity":"f7e81d52-2f32-4fcb-a500-bcd4e4ba510d","added_by":"auto","created_at":"2025-09-02 06:45:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":284492,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient selection. CD, Crohn’s disease; EEN, exclusive enteral nutrition; IFX, infliximab; UST, ustekinumab.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/17b3eb45298a4807a3cf94de.png"},{"id":90380701,"identity":"25d86207-8862-4240-9475-aeacc7338e8d","added_by":"auto","created_at":"2025-09-02 06:45:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":374074,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of CRP and ESR between the EEN and biologics groups at baseline and after treatment in the overall population. EEN, exclusive enteral nutrition; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/3a73390c1320ca0b16176abc.png"},{"id":90380707,"identity":"b9a20be2-241b-40eb-9cff-d84bd42ca030","added_by":"auto","created_at":"2025-09-02 06:45:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":463292,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of BMI, HGB, and ALB between the EEN and biologicsgroups at baseline and after treatment in the overall population. EEN, exclusive enteral nutrition; BMI, body mass index; HGB, hemoglobin; ALB, albumin.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/1539a428ba961409fcd7dcbc.png"},{"id":90380710,"identity":"d6483335-dc43-4e8b-8751-b51c20857d85","added_by":"auto","created_at":"2025-09-02 06:45:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1009329,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of clinical remission(a), clinical response (a), fistula healing (b), transmural healing(b), radiological response(c), CRP normalization(c), endoscopic response (d), and endoscopic remission(d). EEN, exclusive enteral nutrition\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/208ce999a3df79a9ee6957a4.png"},{"id":90797190,"identity":"1265acf8-b5a6-47d6-b581-42f7a53df439","added_by":"auto","created_at":"2025-09-08 09:17:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3022213,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/fbaac1e2-1496-4157-9b7e-b9cd5217d070.pdf"},{"id":90382434,"identity":"40226f07-dbb2-458f-95b4-895e72c49bc9","added_by":"auto","created_at":"2025-09-02 06:53:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":31654,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/74b5b42c9f64b6ea6160d4e6.docx"},{"id":90380730,"identity":"10f06614-cad1-4a4a-a6fa-e71ce0daf3ea","added_by":"auto","created_at":"2025-09-02 06:45:04","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":25235428,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/7393a84db9c2062e8e19db30.tif"},{"id":90380729,"identity":"bb2668fa-abf4-4ff3-b9e9-6a4793d259e4","added_by":"auto","created_at":"2025-09-02 06:45:04","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":26303804,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/5e5b65402ee4ddfb32f271b0.tif"},{"id":90380712,"identity":"c7e7e024-9a88-4cb3-b908-e1fbe086229a","added_by":"auto","created_at":"2025-09-02 06:45:03","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":258456,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7418997/v1/54a2145ac2146bbc097abb75.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Crohn’s disease complicated with intestinal fistulas: Exclusive enteral nutrition or Biologics?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCrohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract that affects the entire intestinal wall.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e A 25-year follow-up study suggested that 29.4% of CD patients progressed from inflammatory behavior to penetrating behavior over 10 years.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Intestinal fistula refers to a pathological connection between the intestine and either the inner or outer epithelial surface, occurring in approximately 16% of adult patients with CD.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e A population-based cohort study has indicated a 33% risk of developing a fistula after 10 years, rising to 50% after 20 years.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The International Organization for the Study of Inflammatory Bowel Disease (IOIBD) has proposed that fistula was the second most important determinant of overall disease severity in CD.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e The presence of intestinal fistulas predicts aggressive disease, reduced quality of life, and early surgery, and its management requires multidisciplinary cooperation, with medical therapy as the cornerstone.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eFor CD patients with a penetrating phenotype, there are standard strategies for abdominal abscesses.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e However, the recommended standard care is lacking in patients with intestinal fistulas without abscesses. Biologic therapies have been the mainstay of medical treatment of fistulizing CD, but the patients enrolled in the study were mostly those with perianal fistulas.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The ACCENT trial, the first and only randomized clinical trial to evaluate biologics in fistulizing CD, included only 38 patients with intestinal fistulas.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e CD patients with intestinal fistulas always presented more severe activity and malnutrition.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eExclusive enteral nutrition (EEN) is a nutritional approach that provides patients with 100% of their nutritional requirements by oral or nasal feeding.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e EEN presented obvious benefits in managing CD, as it effectively induces clinical remission, improves nutritional status, promotes mucosal healing, and reduces levels of proinflammatory cytokines, with minimal adverse effects.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e A previous study in India suggested EEN effectively induced complete healing in active CD patients complicated with enteroenteric fistulae, while the sample is relatively small.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e In our previous studies, EEN is effective in patients with penetrating complications.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e However, EEN is less tolerant in adult patients than in paediatric patients. Choosing the right strategy for the right patient is of great clinical significance. We aimed to compare the efficacy and prognosis between EEN and biologics in adult CD with intestinal fistulas, and to explore the preferred choice of treatment strategy for these patients in clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eThis was a single-center, retrospective, observational cohort study that enrolled CD patients from January 2014 to May 2024. The study was approved by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (E2024065). All procedures were performed under the principles of the Declaration of Helsinki.\u003c/p\u003e\u003cp\u003eThe inclusion criteria were: (1)age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; (2)diagnosed as CD based on clinical, endoscopic, radiological, and pathological manifestations;\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e (3) intestinal fistulas confirmed by radiological imaging[e.g., computed tomography enterography (CTE), magnetic resonance enterography (MRE), bowel ultrasound];\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e (4) active stage; (5) received EEN therapy for 12 weeks or standard biological [e.g., infliximab (IFX) or ustekinumab(UST) ]induction therapy. The following patients were excluded: (1) those with incomplete clinical data; (2) patients in pregnancy or lactation; (3) those requiring emergency surgery; (4) those combined with abdominal abscess or symptomatic intestinal obstruction.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInvestigated drugs\u003c/h3\u003e\n\u003cp\u003eBoth UST and IFX were given at standard-label doses. Intravenous infusions of IFX at a dosage of 5 mg/kg at 0, 2, and 6 weeks were prescribed for inducing remission. UST was initiated with a weight-based intravenous infusion (260 mg\u0026thinsp;\u0026le;\u0026thinsp;55 kg, 390 mg between 55 kg and 85 kg, 520 mg\u0026thinsp;\u0026gt;\u0026thinsp;85 kg) in the induction period, and followed by subcutaneous UST (90 mg every 8 weeks) afterward. In the EEN group, patients received enteral nutrition with an amino acid, peptide, or protein-type formula by nasogastric feeding or orally for 12 weeks. Daily calorie intake was 25\u0026ndash;30 kcal/kg/d.\u003csup\u003e17\u003c/sup\u003e No combination therapies, including steroids and immunosuppressants, were used in these patients.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eThe clinical characteristics at baseline and after therapy were collected from the electronic medical records. Clinical evaluations were performed at weeks 12 to 14 for EEN and IFX, and at weeks 16\u0026ndash;24 for UST. The following data were collected, including sex, age, body mass index (BMI), disease characteristics (e.g., disease location, disease behavior, perianal lesions), upper gastrointestinal involvement, previous surgery history related to CD (including perianal and intestinal surgery), previous medication history, disease activity scores, inflammatory index [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)],nutrition-related index [(hemoglobin (HGB), albumin (ALB)], endoscopic manifestations, ultrasound manifestations, CT or MR manifestations.\u003c/p\u003e\n\u003ch3\u003eDefinition\u003c/h3\u003e\n\u003cp\u003eDisease phenotype was classified according to the Montreal classification.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Disease activity was assessed using the Harvey-Bradshaw Index (HBI). HBI\u0026thinsp;\u0026le;\u0026thinsp;4 was defined as a remission period. HBI ranging from 5\u0026ndash;7, 8\u0026ndash;16, and \u0026gt;\u0026thinsp;16 were defined as mild, moderate, and severe activity. Clinical response was defined by a decrease\u0026thinsp;\u0026ge;\u0026thinsp;3 in HBI score.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Endoscopic response was defined as \u0026ge;\u0026thinsp;50% decrease of SES-CD score, with SES-CD score\u0026thinsp;\u0026le;\u0026thinsp;2 was classified as endoscopic remission\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Radiographic assessment through CTE, MRE, or bowel ultrasound. Radiographic response referred to improvement in intestinal wall thickness, mesenteric inflammatory fat, intestinal wall blood flow, and intestinal wall enhancement signal from baseline.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Radiographic assessment includes active intestinal inflammation (increased bowel wall thickening, presence of ulceration, edema, or increased contrast enhancement), pericentric inflammation (comb sign, enlarged lymph nodes, fat creeping), and CD-related complications (stricture, sinus tract/fistula, abscess or inflammatory mass) for each intestinal segment (jejunum, ileum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum). Given the intra-segment heterogeneity, we measured the most affected section. Transmural healing was defined as no sign of active intestinal inflammation, absence of peri-enteric inflammation, and no CD-related complications\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Simple fistula was classified as a single fistulous tract, and complex fistula was defined as 2 or more fistula tracts,\u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e and fistula healing refers to the disappearance of fistulas observed through various imaging techniques.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e CRP normalization refers to a CRP level\u0026thinsp;\u0026lt;\u0026thinsp;5 mg/L.\u003csup\u003e25\u003c/sup\u003e Surgical treatment included surgeries for penetrating lesions such as intestinal resection, fistula excision, fistula repair, and stomy.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was clinical remission. The secondary outcomes were clinical response, fistula healing, radiological response, transmural healing, endoscopic response, endoscopic remission, CRP normalization, and surgery.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll data were analyzed and processed using SPSS 25.0 (SPSS, Chicago, IL). The Kolmogorov-Smirnov test was used to determine whether the continuous variables were normally distributed. Continuous variables with a normal distribution were represented by the mean and standard deviation (\u0026plusmn;\u0026thinsp;SD), while non-normal continuous variables were represented by the median and interquartile range (IQR). Categorical variables were presented as numbers and percentages (n, %). Continuous variables were compared using the t-test (normal distribution) or the Wilcoxon test (non-normal distribution). Categorical variables were measured by the Chi-square test or Fisher's exact probability method. Univariate and multivariate logistic regression analyses were used to identify predictors affecting clinical remission. Variables with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.2 in the univariate analysis were included in the multivariate analysis. All \u003cem\u003eP-\u003c/em\u003evalues were two-sided, and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003ePatient characteristics at baseline\u003c/h2\u003e\u003cp\u003eA total of 108 patients were included in the study, including 47 cases treated with biologics (27 UST and 20 IFX) and 61 cases with EEN (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThere were no significant differences between the two groups regarding sex, disease duration, and disease characteristics (e.g., age at diagnosis, disease location, disease behavior, perianal lesions, upper gastrointestinal involvement, and previous surgery history). The proportion of previous medication history in the biologics group was significantly higher than that in the EEN group (78.7% vs. 45.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). There were significant differences in the classification of fistula tract (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and type of fistulas (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, the patients in the EEN group showed more moderate-severe activity (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012), higher inflammatory burden (including ESR and CRP), and poorer nutritional status (including BMI, ALB, and HGB) than those in the biologics group (All \u003cem\u003eP-\u003c/em\u003evalues\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\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\u003eThe clinical characteristics of CD patients at baseline\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiologics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEEN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33\u0026nbsp;(70.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40\u0026nbsp;(65.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.610\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease\u0026nbsp;duration (months,\u0026nbsp;median [IQR])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57.0 (25.0, 98.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52.0 (13.0, 97.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.493\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u0026nbsp;at\u0026nbsp;diagnosis (years,\u0026nbsp;median [IQR])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26.0 (20.0,34.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.0\u0026nbsp;(25.5, 35.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.055\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMontreal classification, n (%)\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=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u0026nbsp;at\u0026nbsp;diagnosis\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\u003e0.508\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u0026ndash;16 years old\u0026nbsp;(A1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u0026nbsp;(6.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u0026nbsp;(1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u0026ndash;40\u0026nbsp;years old (A2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37 (78.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51\u0026nbsp;(83.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;\u0026nbsp;40\u0026nbsp;years old (A3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (14.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u0026nbsp;(14.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease\u0026nbsp;location\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=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIleal (L1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7\u0026nbsp;(11.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.320\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIleocolonic (L3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 (95.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54\u0026nbsp;(88.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUpper\u0026nbsp;gastrointestinal\u0026nbsp;involvement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (44.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (42.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.831\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePerianal\u0026nbsp;lesions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38 (80.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44 (72.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.293\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious medication\u0026nbsp;history, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37 (78.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28\u0026nbsp;(45.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCorticosteroids, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17\u0026nbsp;(36.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u0026nbsp;(26.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.266\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEEN, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (59.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (6.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eImmunomodulators, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25\u0026nbsp;(53.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17\u0026nbsp;(27.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBiologics, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (40.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (11.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003ePrevious\u0026nbsp;surgery\u0026nbsp;history, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (53.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 (49.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.679\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious\u0026nbsp;perianal\u0026nbsp;surgery, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (34.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (29.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.615\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious\u0026nbsp;intestinal surgery, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (27.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u0026nbsp;(23.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.575\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClassification of fistula tract, n (%)\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\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSimple fistula\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46 (97.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46 (75.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComplex fistula\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (24.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTypes of fistulas, n/N (%)\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\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnteric fistula\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45/48 (93.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56/76 (73.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnterocutaneous fistula\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/48 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11/76 (14.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVesical fistula\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/48 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9/76 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBI scores at baseline (median [IQR])\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.0 (5.0, 7.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.0 (6.0, 9.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease activity, n (%)\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\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMild activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36 (76.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (45.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModerate activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (23.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32 (52.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere activity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eValues are presented as numbers (%).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eEEN, exclusive enteral nutrition; IQR, interquartile range; HBI, Harvey-Bradshaw Index.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eOutcome measures\u003c/h2\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003eClinical remission and clinical response\u003c/h2\u003e\u003cp\u003eThe rate of clinical remission was 55.3% (26/47) in patients with biologics, and 41% (25/61) in patients with EEN. No differences were found between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.139) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). The baseline HBI (OR 0.75, 95% CI, 0.60\u0026ndash;0.93, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) was negatively correlated with clinical remission (Supplementary Table\u0026nbsp;1). A total of 39 patients in the EEN group (63.9%) and 29 patients in the biologics group (61.7%) achieved clinical response, with no significant differences between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.812) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eFistula healing, transmural healing and radiological response\u003c/h2\u003e\u003cp\u003eA total of 17 CD patients (15.7%) achieved fistula healing. The rate of fistula healing was significantly higher in the EEN group than in the biologics group (23.0% vs. 6.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb). Additionally, the rate of transmural healing was comparable between EEN and biologics group (13.1% vs. 6.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.409) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb). A total of 89 CD patients (82.4%) achieved radiological response, including 32 cases in biologics group (68.1%) and 57 cases in EEN group (93.4%). EEN was superior to biologics in inducing radiological response (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eEndoscopic response and endoscopic remission\u003c/h2\u003e\u003cp\u003eSeventy-three patients (18 UST, 17 IFX, and 38 EEN) completed endoscopic evaluation both at baseline and after treatment. The rate of endoscopic response was comparable between EEN and biologics group (76.3% vs. 62.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.211) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed). There were 21 patients in EEN group (55.3%) and 14 patients in biologics group (40%) who achieved endoscopic remission, with no significant differences between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.192) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eCRP normalization\u003c/h2\u003e\u003cp\u003eThe rate of CRP normalization was significantly higher in EEN group than biologics group (73.8% vs. 55.3%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eSurgery\u003c/h2\u003e\u003cp\u003eThere were 10 patients in EEN group (16.4%) and 1 patient in biologics group (2.1%) underwent surgery, with significant differences between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040). Among patients who underwent surgery in EEN, 70% (7/10) were complex intestinal fistulas. Nine (90%) patients underwent surgery because of intestinal fistula, and two (20%) patients underwent surgery because of intestinal obstruction. Specifically, one patient showed both intestinal fistula and intestinal obstruction simultaneously. One patient received surgery in UST because of complex intestinal fistulas.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eChanges in inflammatory burden and nutritional status\u003c/h2\u003e\u003cp\u003eAfter treatment, the EEN group showed lower CRP level (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) than that in biologics group, Other inflammatory and nutritional indexes were comparable between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup analysis\u003c/h2\u003e\u003cp\u003eIn terms of baseline characteristics, the differences in baseline characteristics between the EEN group and the UST group, as well as between the EEN group and the IFX group, were similar to those between the EEN group and the biologics group. (Supplementary Table\u0026nbsp;2 and Supplementary Table\u0026nbsp;3). Compared to the UST group, the EEN group showed higher inflammatory burden (including ESR and CRP) and poorer nutritional status (including BMI, ALB, and HGB) at baseline, while lower CRP after treatment (All \u003cem\u003eP-\u003c/em\u003evalues\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Supplementary Fig.\u0026nbsp;1 and Supplementary Fig.\u0026nbsp;2). Additionally, the EEN group showed lower BMI (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) at baseline, while higher ALB (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040) after treatment. (Supplementary Fig.\u0026nbsp;1 and Supplementary Fig.\u0026nbsp;2). Notably, EEN was superior to UST in inducing radiological response (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), but other clinical, endoscopic, and radiological outcomes between the EEN group and UST group, as well as between the EEN group and the IFX group were comparable. (Supplementary Table\u0026nbsp;4, Supplementary Table\u0026nbsp;5, and Supplementary Fig.\u0026nbsp;3).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we focused on a specific population lacking recommended standard care, CD patients complicated with intestinal fistulas but not abscesses. The previous study recommended biologics as a non-surgical treatment in these patients.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e However, high-grade evidence supporting this approach remains inadequate. EEN is also effective in patients with complications,\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e but is difficult to follow. In the present study, we found that both EEN and biologics were effective in these patients. For patients with complex intestinal fistulas, more severe activity and malnutrition, EEN may have an advantage.\u003c/p\u003e\u003cp\u003eThe studies of intestinal penetrating CD were rare, for the baseline characteristics were complex in these patients, such as types, number, location and complicated situations of fistulas. In our study, we excluded patients with abscess or symptomatic intestinal obstruction. In these patients, non-surgical treatment is the first choice. To find which strategy is better, we compared two commonly used strategies. The baseline characteristics were significantly different in the two groups, although we tried some methods, such as Propensity Score Matching. It is consistent with the clinical setting after shared decision-making. This clinical decision-making tendency may be related to the efficacy of EEN in improving nutritional status and reducing inflammatory burden. Patients with more severe activity, more complex intestinal fistulas, heavier inflammatory burden, and worse nutritional status tend to accept EEN. Patients treated with EEN showed similar clinical, endoscopic, and radiological efficacy despite more severe disease, compared to patients using biologics. Additionally, EEN showed higher rates of fistula healing and radiological response compared to biological therapy. It is worth noting that the inflammatory burden and nutritional status after treatment were comparable between the biologics group and the EEN group. Our results suggest that both EEN and biologics are effective in CD patients with intestinal fistulas. Given the differences in baseline characteristics, EEN has more advantages in patients with heavier inflammatory burden, more severe disease activity, complex intestinal fistulas, and malnutrition.\u003c/p\u003e\u003cp\u003eA retrospective multicenter cohort study included 760 fistulizing CD receiving biologic therapy, including 673 anti-tumor necrosis factors, 69 UST, and 18 vedolizumab, showed that 24% of patients achieved fistula closure\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. In CD adults with complications, 75% of patients with abdominal fistulas achieved fistula closure after 12 weeks of EEN treatment.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e In the biologics group, all patients who achieved fistula healing were simple fistulas. Similarly, previous studies have reported that in patients with CD complicated with enterocutaneous fistula treated with IFX, the failure of fistula healing is associated with complex fistulas.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e While in patients with EEN, two patients with complex fistulas also achieved fistula healing. Nevertheless, the surgical rate in the EEN group was higher than that in the biologics group. This condition may be related to the higher proportion of patients with complex intestinal fistulas and more severe disease activity in the EEN group. A multicenter retrospective cohort study in France reported that complex intestinal fistulas are associated with surgery.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e We observed that complex intestinal fistulas are the main cause of surgery, similar to previous studies.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e The data from our center indicated that both EEN and biologics can promote fistula healing, but they cannot completely avoid surgery. For complex fistulas, EEN may be a better choice.\u003c/p\u003e\u003cp\u003eIn a Danish multicenter cohort of adult patients treated with anti-tumor necrosis factors, higher baseline HBI was less likely to achieve clinical remission\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Our result also showed that a higher baseline HBI was associated with lower clinical remission in patients with complex intestinal fistulas.\u003c/p\u003e\u003cp\u003eThis study has several limitations. Firstly, due to the respective nature, some baseline characteristics were different in the two groups, which may cause bias. Secondly, the sample size is relatively small, head-to-head comparative studies with large sample sizes are needed to prove our findings in the future.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, EEN and biologics are clinically effective treatments for adult CD with intestinal fistulas, presenting similar clinical remission rate, and they both can achieve endoscopic and radiological improvement. However, the intolerance of EEN limits its application in some patients, and biologics are preferred for these patients in clinical practice. For patients with complex intestinal fistulas, more severe disease, and malnutrition, EEN may be a good choice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCrohn's disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIOIBD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInternational Organization for the Study of Inflammatory Bowel Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEEN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eExclusive enteral nutrition\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCTE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eComputed tomography enterography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic resonance enterography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIFX\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInfliximab\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUST\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUstekinumab\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebody mass index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eC-reactive protein\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eESR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eErythrocyte sedimentation rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHGB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHemoglobin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAlbumin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eStandard deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInterquartile range\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHBI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHarvey-Bradshaw Index (HBI)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConfidence interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOdds ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (E2024065). All procedures were performed under the principles of the Declaration of Helsinki. Written informed consent was waived due to the retrospective study design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by the National Key R\u0026amp;D Program of China (2023YFC2507300), National Natural Science Foundation of China (No.82470570), and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCK and TJ contributed to the study design. YQF and HZC were responsible for patient recruitment. DXX, HZP, JWZ, WYH, and DN performed data collection. DXX, HZP, and JWZ\u0026nbsp;conducted the data analysis. GQ, LM, and YHS provided supervision throughout the development of the study. GX administered the project. CK and YQF reviewed and revised the manuscript.\u0026nbsp;All authors approved the final version of the manuscript including the authorship list. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSingh S, Proctor D, Scott FI, Falck-Ytter Y, Feuerstein JD. AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing. Crohn's Disease Gastroenterol. 2021;160(7):2512\u0026ndash;e25562519.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLouis E, Collard A, Oger AF, et al. Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course. disease Gut. 2001;49(6):777\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHirten RP, Shah S, Sachar DB, Colombel JF. The Management of Intestinal Penetrating Crohn's Disease. Inflamm Bowel Dis. 2018;24(4):752\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchwartz DA, Loftus EV, Tremaine WJ, et al. The natural history of fistulizing Crohn's disease in Olmsted County. Minn Gastroenterol. 2002;122(4):875\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSiegel CA, Whitman CB, Spiegel BMR, et al. Development of an index to define overall disease severity in. IBD Gut. 2018;67(2):244\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLevy C, Tremaine WJ. Management of internal fistulas in Crohn's disease. Inflamm Bowel Dis. 2002;8(2):106\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCasas Deza D, Polo Cuadro C, de Francisco R, et al. Initial Management of Intra-abdominal Abscesses and Preventive Strategies for Abscess Recurrence in Penetrating Crohn's Disease: A National, Multicentre Study Based on ENEIDA Registry. J Crohns Colitis. 2024;18(4):578\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee MJ, Parker CE, Taylor SR, et al. Efficacy of Medical Therapies for Fistulizing Crohn's Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(12):1879\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease.N Engl. J Med. 2004;350(9):876\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu Y, He Y, Chen F, et al. [Nutritional risk screening in patients with Crohn's disease]. Zhonghua Yi Xue Za Zhi. 2016;96(6):442\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFansiwala K, Shah ND, McNulty KA, Kwaan MR, Limketkai BN. Use of oral diet and nutrition support in management of stricturing and fistulizing Crohn's disease. Nutr Clin Pract. 2023;38(6):1282\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHartman C, Eliakim R, Shamir R. Nutritional status and nutritional therapy in inflammatory bowel diseases. World J Gastroenterol. 2009;15(21):2570\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSood A, Singh A, Sudhakar R, et al. Exclusive enteral nutrition for induction of remission in anti-tumor necrosis factor refractory adult Crohn's disease: the Indian experience. Intest Res. 2020;18(2):184\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang Q, Gao X, Chen H, et al. Efficacy of exclusive enteral nutrition in complicated Crohn's disease. Scand J Gastroenterol. 2017;52(9):995\u0026ndash;1001.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eM'Koma AE. Inflammatory Bowel Disease: Clinical Diagnosis and Surgical Treatment-Overview.Medicina. (Kaunas) 2022;58(5).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchmidt S, Chevallier P, Bessoud B, et al. Diagnostic performance of MRI for detection of intestinal fistulas in patients with complicated inflammatory bowel conditions. Eur Radiol. 2007;17(11):2957\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuo Z, Wu R, Zhu W, et al. Effect of exclusive enteral nutrition on health-related quality of life for adults with active Crohn's disease. Nutr Clin Pract. 2013;28(4):499\u0026ndash;505.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSatsangi J, Silverberg MS, Vermeire S, Colombel JF, Gut. 2006;55(6):749\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKotze PG, Ma C, Almutairdi A, et al. Real-world clinical, endoscopic and radiographic efficacy of vedolizumab for the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2018;48(6):626\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDaperno M, D'Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLafeuille P, Hordonneau C, Vignette J, et al. Transmural healing and MRI healing are associated with lower risk of bowel damage progression than endoscopic mucosal healing in Crohn\u0026rsquo;s disease. Aliment Pharmacol Ther. 2020;53(5):577\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAmiot A, Setakhr V, Seksik P, et al. Long-term outcome of enterocutaneous fistula in patients with Crohn's disease treated with anti-TNF therapy: a cohort study from the GETAID. Am J Gastroenterol. 2014;109(9):1443\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBouguen G, Huguet A, Amiot A, et al. Efficacy and Safety of Tumor Necrosis Factor Antagonists in Treatment of Internal Fistulizing Crohn's Disease. Clin Gastroenterol Hepatol. 2020;18(3):628\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMa Y, Zhang R, Liu W, et al. Prognostic factors for the efficacy of infliximab in patients with luminal fistulizing Crohn's disease. BMC Gastroenterol. 2023;23(1):57.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWilkens R, Novak KL, Maaser C, Panaccione R, Kucharzik T. Relevance of monitoring transmural disease activity in patients with Crohn's disease: current status and future perspectives. Th Adv Gastroenterol. 2021;14:17562848211006672.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing. Crohn's disease Gastroenterol. 2005;128(4):862\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJones DW, Finlayson SRG. Trends in Surgery for Crohn's Disease in the Era of Infliximab. Ann Surg. 2010;252(2):307\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTjandra D, Garg M, Behrenbruch C, et al. Review article: investigation and management of internal fistulae in Crohn's disease. Aliment Pharmacol Ther. 2021;53(10):1064\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBarreiro-de Acosta M, Fern\u0026aacute;ndez-Clotet A, Mesonero F, et al. Long-Term Outcomes of Biological Therapy in Crohn's Disease Complicated With Internal Fistulizing Disease: BIOSCOPE Study From GETECCU.Am. J Gastroenterol. 2023;118(6):1036\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhao M, Larsen L, Dige A et al. Clinical outcomes after first-line anti-TNF treatment of patients with inflammatory bowel disease - a prospective multicenter cohort study. J Crohns Colitis 2025;19(5).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Exclusive enteral nutrition, Biologics, Active Crohn’s disease, Intestinal fistulas","lastPublishedDoi":"10.21203/rs.3.rs-7418997/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7418997/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eApproximately 16% of adult patients with Crohn's disease (CD) are complicated with intestinal fistulas. Both exclusive enteral nutrition (EEN) and biologics have shown potential efficacy. We aimed to compare the efficacy of EEN and biologics in adult CD with intestinal fistulas and to explore the preferred choice for these patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis single-center, retrospective study involved adult CD patients with active intestinal fistulas who received EEN or biologics induction therapy from January 2014 to May 2024. Exclusion criteria included concurrent abdominal abscesses or symptomatic intestinal obstruction. The primary endpoint was clinical remission. The secondary outcomes encompassed clinical response, radiological response, transmural healing, fistula healing, endoscopic response, endoscopic remission, C-reactive protein (CRP) normalization, and surgery.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 108 patients (47 biologics and 61 EEN) were enrolled. At baseline, the EEN group exhibited more complex intestinal fistulas, higher inflammatory burden, and poorer nutritional status compared to the biologics group. The EEN group showed higher rates of fistula healing (23% vs. 6.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019), radiological response (93.4% vs. 68.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), CRP normalization (73.8% vs. 55.3%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045), and surgery (16.4% vs. 2.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eEEN and biologics are clinically effective treatments for adult CD patients with intestinal fistulas. Biologics are preferred for patients without tolerance of EEN. EEN is preferred for patients with complex intestinal fistulas, severe activity, and malnutrition.\u003c/p\u003e","manuscriptTitle":"Crohn’s disease complicated with intestinal fistulas: Exclusive enteral nutrition or Biologics?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-02 06:44:58","doi":"10.21203/rs.3.rs-7418997/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"80226340-ac92-406d-8bca-5fa7ac024440","owner":[],"postedDate":"September 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T09:09:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-02 06:44:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7418997","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7418997","identity":"rs-7418997","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}