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Purpose: Patients with Crohn’s disease (CD) frequently undergo multiple abdominal operations, which increase the risk of incisional hernia repair (IHR) and associated mesh-related complications. Patients with intra-abdominal fistulizing CD (FCD) may be more susceptible to mesh-related complications than patients with non-fistulizing CD (non-FCD). The primary objective was to evaluate the risk of reoperation due to mesh-related complications after IHR in patients with FCD and non-FCD. Secondarily, the study evaluated the impact of isolated perianal fistulizing CD on mesh-related complications and the difference in hernia recurrence reoperation rates between FCD and non-FCD patients. Methods: This nationwide study followed patients from 30 days after their first recorded IHR until reoperation due to mesh-related complications or hernia recurrence. Cumulative incidence proportion and Cox regression analysis were used to estimate the risk of these outcomes. Results: A total of 334 patients with CD (FCD, n = 55; non-FCD, n = 279) underwent IHR between 2007 and 2016 with a follow-up rate of 100%. FCD patients had a significantly higher 5 year risk of reoperation for mesh-related complications (HR 15.95, 95% CI 4.29–59.35) compared with non-FCD patients. None of the patients with isolated perianal fistulizing disease required a reoperation for mesh-related complications. The overall risk of reoperation for recurrence was 8.7%, and did not vary significantly between FCD and non-FCD patients (HR 1.06, 95% CI 0.44–2.58). Conclusions: FCD may be associated with higher rates of mesh-related complications compared with non-FCD, although larger studies are needed to confirm this finding. Conversely, isolated perianal fistulas do not appear to be associated with an increased risk of mesh-related complications. The benefits associated with mesh should be balanced with the risk of long-term mesh-related complications in patients with FCD. [ABSTRACT FROM AUTHOR]

Background Managing complex perianal fistulizing Crohn's disease (CD) remains challenging, despite current medical and surgical treatment approaches. Darvadstrocel, a therapy utilizing adipose-derived stem cells, shows promise in promoting tissue regeneration and healing, offering a novel and effective treatment for fistula management. Method A systematic literature search was conducted on PubMed and Scopus to identify studies involving patients with complex perianal fistulizing CD treated with darvadstrocel. Results In total, 2 randomized controlled trials (RCT), 5 observational studies with retrospective data collection and 2 observational studies with prospective design were included in the final review. Data from the European ADMIRE-CD RCT demonstrated that darvadstrocel is superior to placebo in terms of clinical and imaging improvement over both the short and long term. These findings align with the prospective studies analyzed in this systematic review. The rate of treatmentemergent adverse events in the ADMIRE-CD trial's RCTs was similar in both the darvadstrocel and control groups, with perianal abscess being the most common adverse event up to 52 weeks after drug administration. Retrospective studies indicated no side-effects beyond 52 weeks. Conclusions Darvadstrocel appears to be a new, potentially effective and safe treatment option for the management of complex perianal fistulas. However, more randomized clinical trials are needed to evaluate the efficacy and safety profile of the drug. [ABSTRACT FROM AUTHOR]

Perianal fistulizing Crohn's Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease (CD) patients often encounter perianal fistula formation, which can cause significant morbidity. Chronic transmural bowel inflammation in CD can lead to sinus tracts evolving into fistulas--abnormal connections between epithelial surfaces. Roughly 35-40% of patients develop fistulas, primarily perianal (54%), with internal fistulas posing diagnostic and therapeutic challenges. Fistulizing CD manifests severe symptoms, affecting quality of life and necessitating frequent hospitalizations and surgeries. Aim of the Work: The aim of the work was to develop risk prediction and identify outcomes of management in fistulizing Crohn's disease. Patients and Methods: This case-control study encompassed 90 Egyptian CD patients, divided into two groups: those with fistulas (external or internal) and those without. Patients were recruited from the Ain Shams outpatient clinic and Gastroenterology and Hepatology department. Clinical, radiological (CT or MR enterography), and colonoscopic assessments were performed. Risk factors, clinical characteristics, and treatment outcomes were examined. Results: In the study, males were more prevalent in the fistula group; however, the difference wasn't statistically significant. Similarly, age and smoking differences were not statistically significant between the study groups. Entero-Entero fistulas were the most common, with Remicade and surgery being the predominant management strategy. NSAID intake significantly correlated with the fistula group. CDAI scores were higher in the fistula group but improved significantly with treatment in both groups. While colonoscopy findings varied minimally before and after treatment, cecum lesions showed significant increase post-treatment in the fistula group. No significant differences existed in outcomes according to management strategy within the fistula group. Conclusion: In conclusion, this study underscores the heightened risk of NSAID intake in fistulizing Crohn's disease, emphasizes the effectiveness of CDAI scores in assessing disease activity and monitoring treatment outcomes, and highlights the importance of personalized management strategies for fistula patients. The significant increase in cecum lesions after treatment within the fistula group suggests the need for focused attention to this aspect. However, the study's limited scope on Egyptian CD patients calls for careful consideration when applying these findings to broader populations. [ABSTRACT FROM AUTHOR]

Background/Aims Exclusive enteral nutrition (EEN) is recommended for induction of remission in pediatric Crohn’s disease (CD). However, it is not currently recommended for inducing remission in adults. This report describes the use of 12-week EEN for induction of remission in anti-tumor necrosis factor (anti-TNF) refractory adult CD. Methods This is a retrospective analysis of adults with moderate to severe active (Crohn’s Disease Activity Index [CDAI] >220) anti-TNF refractory CD, who received EEN for 12 weeks between April 2018 and March 2019 at Dayanand Medical College and Hospital, Ludhiana, India. Primary outcomes included achievement of clinical remission and fistula healing at 12 weeks. Improvement in inflammatory markers and nutritional status were the secondary end points. Results Out of 23 patients who received anti-TNF agents, 7 (30.4%) were refractory and were offered EEN as a salvage therapy. Six patients (66.7% females, mean age 25.6±6.5 years) consented. Four patients (66.6%) achieved clinical remission (CDAI 50%), though none achieved remission. Entero-enteric fistulae showed complete healing. Mean body mass index improved from 15.6±3.1 to 18.9±1.9 kg/m2 at week 12 (P=0.003). Hemoglobin and serum albumin also improved from 8.2±1.1 g/dL and 2.8±0.3 g/dL at baseline to 12.6±0.6 g/dL and 3.6±0.5 g/dL post-EEN respectively (P

Perianal fistulizing Crohn’s Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future.

Crohn’s disease (CD) is a chronic immune-mediated inflammatory condition caused by the loss of mucosal tolerance toward the commensal microbiota. On average, 29.5% and 42.7% CD patients experience perianal complications at 10 and 20 y after diagnosis, respectively. Perianal CD (pCD) result in high disease burden, diminished quality of life, and elevated health-care costs. Overall pCD are predictors of poor long-term outcomes. Animal models of gut inflammation have failed to fully recapitulate the human manifestations of fistulizing CD. Here, we evaluated dogs with spontaneous canine anal furunculosis (CAF), a disease with clinical similarities to pCD, as a surrogate model for understanding the microbial contribution of human pCD pathophysiology. By comparing the gut microbiomes between dogs suffering from CAF (CAF dogs) and healthy dogs, we show CAF-dog microbiomes are either very dissimilar (dysbiotic) or similar (healthy-like), yet unique, to healthy dog’s microbiomes. Compared to healthy or healthy-like CAF microbiomes, dysbiotic CAF microbiomes showed an increased abundance of Bacteroides vulgatus and Escherichia coli and a decreased abundance of Megamonas species and Prevotella copri. Our results mirror what have been reported in previous microbiome studies of patients with CD; particularly, CAF dogs exhibited two distinct microbiome composition: dysbiotic and healthy-like, with determinant bacterial taxa such as E. coli and P. copri that overlap what it has been found on their human counterpart. Thus, our results support the use of CAF dogs as a surrogate model to advance our understanding of microbial dynamics in pCD.

Background/Aims: Exclusive enteral nutrition (EEN) is recommended for induction of remission in pediatric Crohn's disease (CD). However, it is not currently recommended for inducing remission in adults. This report describes the use of 12-week EEN for induction of remission in anti-tumor necrosis factor (anti-TNF) refractory adult CD. Methods: This is a retrospective analysis of adults with moderate to severe active (Crohn's Disease Activity Index [CDAI] > 220) anti-TNF refractory CD, who received EEN for 12 weeks between April 2018 and March 2019 at Dayanand Medical College and Hospital, Ludhiana, India. Primary outcomes included achievement of clinical remission and fistula healing at 12 weeks. Improvement in inflammatory markers and nutritional status were the secondary end points. Results: Out of 23 patients who received anti-TNF agents, 7 (30.4%) were refractory and were offered EEN as a salvage therapy. Six patients (66.7% females, mean age 25.6 ± 6.5 years) consented. Four patients (66.6%) achieved clinical remission (CDAI < 150). Mean CDAI of patients decreased significantly after 12 weeks of EEN (388.8 ± 74.8 vs. 160.0 ± 25.2, P< 0.001). Perianal fistulas showed clinical response (drainage decreased by > 50%), though none achieved remission. Entero-enteric fistulae showed complete healing. Mean body mass index improved from 15.6 ± 3.1 to 18.9 ± 1.9 kg/m2 at week 12 (P= 0.003). Hemoglobin and serum albumin also improved from 8.2 ± 1.1 g/dL and 2.8 ± 0.3 g/dL at baseline to 12.6 ± 0.6 g/dL and 3.6 ± 0.5 g/dL post-EEN respectively (P< 0.001 and P= 0.006 respectively). Conclusions: EEN appears to be an effective and well tolerated therapy for induction of remission in anti-TNF refractory adult CD. More data from prospective trials with larger number of patients is required. [ABSTRACT FROM AUTHOR]

Minimally invasive approaches are safe, feasible, and often recommended as the initial choice in the surgical management of Crohn's disease. However, a consensus has not been reached as the ideal approach in the surgical treatment of complex and recurrent Crohn's disease. Laparoscopy may provide advantages such as shorter length of stay and decreased postoperative pain and result in less adhesion formation in patients with complex disease. Robotic techniques may be beneficial in selected patients for completion proctectomy, providing better visualization in the narrow pelvis and increased dexterity. Decision of surgical technique should be made on a case-by-case basis. [ABSTRACT FROM AUTHOR]

Medical treatment for fistulizing Crohn's disease (FCD) is changing rapidly over the time by the introduction of novel therapeutic medicines, while no global consensus is available. This study aims to accomplish a systematic review and meta-analysis on the efficacy of tumor necrosis factor-alpha antibodies (anti-TNF-α antibodies) versus placebo in FCD. A systematic review of published literature was carried out till December 2016, and a meta-analysis of identified studies was done. Data have been explored from PubMed, Scopus, Cochrane Library Database, and Web of Science. Predefined exclusion criteria for included studies in meta-analysis are based on search methodology and are as follows: Randomized clinical trial about Crohn's disease (CD) patients without fistula, pediatrics CD, randomized clinical trials about pregnant women with FCD, nonhuman studies, randomized clinical trials with surgical therapies interventions, conference abstracts, case reports, and language other than English studies. All randomized placebo-controlled trials were included. To assess risk of bias, Jadad score was applied to evaluate trials' methodological quality. Relative risk (RR) and 95% confidence intervals were computed using Mantel-Haenszel and/or Rothman-Boice (for fixed effects) or Der Simonian-Laird (for random effects) techniques. Nine studies attained defined inclusion criteria. The meta-analysis results showed that anti-TNF-α antibodies are remarkably more effective in comparison to placebo for fistula closure maintenance (RR = 2.36; 95% confidence interval: 1.58–3.55; P < 0.0001) in patients with FCD, whereas anti-TNF-α antibodies were not superior to placebo neither in fistula improvement nor in fistula closure. We concluded that adalimumab and certolizumab pegol are both effective in fistula closure maintenance in adult patients with FCD.

In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying process but also death-independent functions that may shape the immunogenicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs undergoing apoptosis and identified several immunomodulatory factors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human T cell proliferation and activation, and chemoattracted monocytes in vitro. Both immunomodulatory activities were dependent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's disease (CD) patients who had undergone MSC treatment (ADMIRE-CD). Compared with healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mechanism whereby caspase activation delivers ApoMSC immunosuppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical responses to MSC therapy in CD., Competing Interests: Declaration of interests A.A. and O.R. are employees of Takeda and hold Takeda stock/stock options. R.H. and F.D. are employees of AstraZeneca. R.C. is a member of the Advisory Board of Takeda on the use of MSC in fistulizing Crohn’s disease. This study did not receive any funding from Takeda or any other pharmaceutical companies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: to evaluate the efficacy and toxicity of infliximab for the treatment of fistulizing Crohn's disease. Methods: consecutive patients with fistulizing Crohn's disease receiving infliximab were prospectively enrolled. Partial response was defined as a reduction of 50% or more from base-line in the number of draining fistulae. Complete response was defined as the closure of all fistulae. The influence of different variables on the efficacy of infliximab was evaluated. Results: 108 patients were included. The disease was inflammatory plus fistulizing in 18% and only fistulizing in 82%. After the third infusion of infliximab the response was partial in 26% and complete in 57%. Response (%) rates (partial/complete) depending on fistula location were: enterocutaneous (25/68%), perianal (35/60%), rectovaginal (36/64%), and enterovesical (20/40%). None of the studied variables (including concomitant immunosuppressive therapy) correlated with efficacy of infliximab in the multivariate analysis. Incidence of adverse effects (21%) depending on the dose of infliximab was: first dose (5.6%), second (7.4%), and third (11.1%). Conclusions: infliximab is an efficacious treatment for fistulizing Crohn's disease. Partial response was achieved in approximately one third of the patients, and complete response in more than half. No studied variable was predictive of response. Adverse effects were relatively infrequent and mild.Objetivo: evaluar la eficacia e identificar los factores predictivos de respuesta al tratamiento con infliximab en la enfermedad de Crohn fistulizante. Métodos: se realizó un estudio prospectivo en pacientes con enfermedad de Crohn fistulizante que recibían tratamiento con infliximab. La respuesta parcial se definió como una reducción del 50% o más de la línea base en el número de fístulas que drenan. La respuesta completa se definió como el cierre de todas las fístulas. Se evaluó la influencia de diferentes variables sobre la eficacia de infliximab. Resultados: se estudiaron 108 pacientes. La enfermedad era inflamatoria y fistulizante en el 18% y sólo fistulizante en el 82%. Después de la tercera infusión de infliximab la respuesta fue parcial en el 26% y completa en el 57%. Las tasas de respuesta (%) (parcial/completa) dependiendo de la localización de la fístula fueron: enterocutánea (25/68%), perianal (35/60%), rectovaginal (36/64%), y enterovesical (20/40%). Ninguna de las variables estudiadas (edad, sexo, tabaco, tratamiento inmunosupresor, antigüedad, origen y localización de la fístula) presentó correlación con la eficacia de infliximab en el análisis de multivariante. La incidencia de efectos adversos (21%) fue: 5,6,7,4 y 11,1% durante la primera, segunda y tercera dosis respectivamente. Conclusiones: infliximab es un tratamiento eficaz para la enfermedad de Crohn fistulizante. Aproximadamente un tercio de los pacientes alcanzaron respuesta parcial y alrededor de la mitad, respuesta completa. Ninguna variable estudiada fue predictiva de respuesta. Los efectos adversos fueron relativamente infrecuentes y leves.

Perianal fistula is a complication of Crohn's disease that carries a high morbidity. It is a channel that develops between the lower rectum, anal canal and perianal or perineal skin. The development of perianal fistulas typically connotes a more aggressive disease phenotype and may warrant escalation of treatment to prevent poor outcomes over time. Based on fistula anatomy, debris can form inside these tracts and cause occlusion, which subsequently leads to abscess formation, fever and malaise. The clinical presentation is often with complaints of pain, continuous rectal drainage of fecal matter as well as malodorous discharge. Considering that the presence of fistulas often indicates refractory and aggressive disease, early identification of its presence is important. Some patients may not have the classic symptoms of fistulizing disease at presentation and others may have significant scarring and/or pain from previous fistulizing episodes, which can make an accurate assessment on physical exam alone problematic. As a result, utilizing diagnostic imaging is the best means of identifying the early signs of perianal fistulas or abscess formation in these patients. Several imaging modalities exist which can be used for diagnosis and management. Endoscopic ultrasound and pelvic MRI are considered the most useful in establishing the diagnosis. However, a combination of multiple imaging modalities and/or examination under anesthesia is probably the most ideal. Incomplete characterization of the fistula tract(s) extent or the presence of abscess carries a high morbidity and far-reaching personal expense for the patient - promoting worsening of the disease. [ABSTRACT FROM AUTHOR]

Antibody-neutralization studies have implicated tumor necrosis factor-α (TNF-α) and IL-12 p40 in the pathogenesis of Crohn′s disease (CD). Many randomized controlled trials (RCTs) have demonstrated the efficacy of infliximab, a chimeric monoclonal antibody to TNF, in inducing and maintaining disease remission in patients with moderate to severe CD, including those with draining fistulas. However, infliximab is administered intravenously and is associated with immunological reactions and development of antibodies, and hence reduced efficacy. In this article, we describe the efficacy and safety profiles of a newly available recombinant, fully humanized, subcutaneously-administered, anti-TNF-α monoclonal antibody, adalimumab (Humira) in patients with moderate to severe CD. Many recent RCTs have shown that adalimumab is not only similar to infliximab in the mode of action, efficacy, and safety, but it has the advantages of causing less anaphylactic or immunological reactions, being administered by the subcutaneous route, less need for hospitalization, and a half-life of 2 weeks that allows every other week dosage. Adalimumab has also shown some efficacy in infliximab-intolerant or resistant cases. Therefore, it represents a new horizon in the treatment of CD patients, and may reduce the number of patients who require surgical intervention.

Purpose: The management of perianal fistula in patients with Crohn's disease is an extremely challenging medical problem as many fistulas do not respond to available treatments. The objectives were to assess the safety and efficacy of a suspension of expanded adipose-derived allogeneic mesenchymal stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease Methods: An open-label, single-arm clinical trial was conducted at six Spanish hospitals. Twenty-four patients were administered intralesionally with 20 million eASCs in one draining fistula tract. A subsequent administration of 40 million eASCs was performed if fistula closure was incomplete at week 12. Subjects were followed until week 24 after the initial administration. Results: Treatment-related adverse events did not indicate any clinical safety concerns after 6 months follow-up. The full analysis of efficacy data at week 24 showed 69.2 % of the patients with a reduction in the number of draining fistulas, 56.3 % of the patients achieved complete closure of the treated fistula achieved, and 30 % of the cases presenting complete closure of all existing fistula tracts. Of note, closure was strictly defined as: absence of suppuration through the external orifice and complete re-epithelization, plus absence of collections measured by magnetic resonance image scan (MRI). Furthermore, MRI Score of Severity showed statistically significant differences at week 12 with a marked reduction at week 24. Conclusions: Locally injected eASCs appear to be a simple, safe, and beneficial therapy for perianal fistula in Crohn's disease patients. Additional studies are needed to further confirm the efficacy of the eASCs. [ABSTRACT FROM AUTHOR]

Introduction A potential protective role of Helicobacter pylori (HP) infection against the development of Crohn's disease (CD) has been postulated. There is a lack of studies evaluating the association of HP with CD phenotypes. The aim of this study was to investigate the clinical features and disease activity of patients with CD who were diagnosed with HP infection. Methods The charts of 306 consecutive patients from the inflammatory bowel disease (IBD) database at the University of Florida College of Medicine, Jacksonville from January 2014 to July 2016 were reviewed. Ninety-one CD patients who were tested for HP were included, and the frequencies of strictures, fistulas, and colitis in surveillance biopsies in these patients were evaluated. Results Of the 91 CD patients tested for HP, 19 had HP infection. A total of 44 patients had fistulizing/stricturing disease, and 62 patients had active colitis. In the univariate analysis, patients with HP infection had less fistulizing/stricturing disease (21.1% vs. 55.6%, p  = 0.009) and less active colitis (42.1% vs. 77.1%, p  = 0.005). In the multivariate analysis, HP infection remained as a protective factor for fistulizing/stricturing disease phenotype (OR: 0.22; 95%CI: 0.06-0.97; p  = 0.022) and active colitis (OR: 0.186; 95%CI: 0.05-0.65; p  = 0.010). Conclusion HP infection was independently associated with less fistulizing/stricturing disease and less active colitis in CD patients. Our study suggests CD patients with a history of HP infection are less prone to complications., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2019, Fialho et al.)