Clinical trial: The effectiveness of long-acting somatostatin analogue for output reduction of high-output intestinal fistula or small bowel enterostomy. A randomised controlled trial.

BACKGROUND: High-output intestinal fistulas and small bowel enterostomies are associated with morbidity and mortality. Current standard treatment for output reduction consists of fluid and dietary restrictions and medical therapy. There is conflicting evidence regarding the use of somatostatin analogues for output reduction. AIM: The aim of this study is to investigate whether lanreotide, added to current standard treatment, further reduces intestinal output in patients with high-output fistulas and enterostomies. METHODS: This was an open-label, multicentre, randomised controlled trial. Adult patients with a high-output intestinal fistula (>500 mL/24 h) or small bowel enterostomy (>1500 mL/24 h) more than 4 weeks post-surgery and receiving standard medical treatment (dietary- and fluid restriction, PPI, loperamide and codeine) for at least 2 weeks were eligible for inclusion. We randomised patients 1:1 between continuing standard treatment (control), and subcutaneous lanreotide 120 mg every 4 weeks with standard treatment. The primary outcome was the number of responders, with response defined as an output reduction of ≥25%, 8 weeks after randomisation. We also investigated the proportional change in output. RESULTS: We randomised 40 patients; 17 had a fistula and 23 a small bowel enterostomy. There were 9/20 responders in the intervention group and 2/20 in the control group (p = 0.013). The proportional output reduction was -26% (IQR -4 to -38) in the intervention group, compared to an increase of 4% (IQR 20 to -13) in the control group (p = 0.004). CONCLUSIONS: In patients with a high-output fistula or small bowel enterostomy, addition of lanreotide to current standard treatment can provide a clinically relevant output reduction. TRIAL REGISTRATION: EudraCT: 2013-003998-10.

The potential for medical therapies to address fistulizing Crohn's disease: a state-of-the-art review.

INTRODUCTION: Crohn's disease (CD) is a chronic, relapsing immune mediated disease, which is one of the two major types of inflammatory bowel disease (IBD). Fistulizing CD poses a significant clinical challenge for physicians. Effective management of CD requires a multidisciplinary approach, involving a gastroenterologist and a GI surgeon while tailoring treatment to each patient's unique risk factors, clinical representations, and preferences. AREAS COVERED: This comprehensive review explores the intricacies of fistulizing CD including its manifestations, types, impact on quality of life, management strategies, and novel therapies under investigation. EXPERT OPINION: Antibiotics are often used as first-line therapy to treat symptoms. Biologics that selectively target TNF-α, such infliximab (IFX), have shown high efficacy in randomized controlled trials. However, more than 50% of patients lose response to IFX, prompting them to explore alternative strategies. Current options include adalimumab and certolizumab pegol combination therapies, as well as small-molecule drugs targeting Janus kinases such as Upadacitinib. Furthermore, a promising treatment for complex fistulas is mesenchymal stem cells such as Darvadstrocel (Alofisel), an allogeneic stem cell-based therapy. However, surgical interventions are necessary for complex cases or intra-abdominal complications. Setons and LIFT procedures are the most common surgical options.

Teduglutide for the treatment of low-output enterocutaneous fistula - A pilot randomized controlled study.

BACKGROUND & AIMS: Enterocutaneous fistula (ECF) is a complication of surgery or inflammatory bowel disease associated with disproportionately high healthcare costs, morbidity, and mortality. We performed this proof-of-concept, feasibility, open-label, pilot randomized, crossover study to assess the efficacy and safety of the use of teduglutide (TED) to treat ECF. METHODS: Adults (age >18) with low-output (<200 mL/d) ECF were randomized to 2 months of continuing standard-of-care (SOC) followed by crossover to 2 months of SOC + TED or the reverse order. The primary efficacy endpoint was decrease in fistula volume by 20% of baseline 3-day average. Secondary efficacy endpoints were: fistula resolution and health-related quality of life questionnaire scores. RESULTS: Six out of 10 planned subjects were randomized and completed the study, which was terminated early due to slow enrollment during the Covid-19 pandemic. Overall subject compliance with daily TED injections was high (98%). Five of six enrolled subjects met the definition for the primary efficacy endpoint; these clinical responses were not observed during the SOC arm in these subjects. One subject experienced complete fistula closure during TED treatment. Adverse events during treatment were uncommon, minor, and usually resolved despite ongoing treatment. Quality of life survey responses were highly variable and did not correlate with fistula changes. CONCLUSIONS: Two months of teduglutide treatment was feasible, well-tolerated, and resulted in observable decreases in ECF drainage in the majority of subjects, including spontaneous closure in one subject. This therapy shows promise, but larger, multicenter confirmatory trials are required. CLINICALTRIALS: GOV: (NCT02889393).

MMP9 expression in intestinal fistula from patients with fistulizing CD and from human xenograft mouse model.

Fistula treatment represents a major unmet medical need in the therapy of Crohn's disease (CD). Current medical therapies, such as anti-TNF antibody treatments, are often insufficient and do not achieve permanent fistula closure. Previously published data point toward a critical role for metalloproteinase-9 (MMP-9)/gelatinase B in fistula pathogenesis. The aim of this project was to investigate in detail MMP-9 expression in different fistula types and to confirm that MMP-9 is a potential target for fistula therapy in CD patients.Immunohistochemistry for total and active MMP-9, Cytokeratin 8 (CK-8) and co-staining of active MMP-9/CK-8 was performed in specimen derived from perianal fistulas, entero-enteric fistulas and fistulas from patients not responding to anti-TNF therapy. In addition, fistulas from the xenograft mouse model (anti-TNF treated or untreated) were analyzed.Total and active MMP-9 protein was detectable in cells lining the tracts of perianal and entero-enteric fistulas. Of note, total and active MMP-9 was also expressed in fistulas of CD patients non-responding to anti-TNF treatment. Interestingly, we detected considerable co-staining of active MMP-9 and CK-8 in particular in cells lining the fistula tract and in transitional cells around the fistulas. Furthermore, total and active MMP-9 are detectable in both anti-TNF treated and untreated xenograft fistulas.Taken together, our data suggest that MMP-9 is involved in fistula pathogenesis in CD patients, in fistulas of different origins and particularly in patients non-responding to anti-TNF therapy. Our xenograft fistula model is suitable for in vivo studies investigating a possible therapeutic role for MMP-9 targeting as fistula therapy.

Higher Postinduction Infliximab Concentrations Are Associated With Improved Clinical Outcomes in Fistulizing Crohn's Disease: An ACCENT-II Post Hoc Analysis.

INTRODUCTION: There are only limited data regarding the role of therapeutic drug monitoring in fistulizing Crohn's disease (CD). We investigated the association between both induction and maintenance serum infliximab concentrations and favorable therapeutic outcomes in patients with fistulizing CD. METHODS: This was a post hoc analysis of the ACCENT-II trial evaluating patients with fistulizing CD receiving induction (n = 282) and maintenance infliximab therapy (n = 139). Investigated therapeutic outcomes at both week 14 and week 54 included fistula response, complete fistula response, C-reactive protein (CRP) normalization (≤5 mg/L) in patients with an elevated baseline CRP, and a more stringent outcome of composite remission, defined as combined complete fistula response and CRP normalization. Associations between serum infliximab concentrations and outcomes were assessed by multivariable logistic regression models. RESULTS: Higher week 14 infliximab concentrations were independently associated with week 14 fistula response (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.02-1.32; P = 0.019), and composite remission (OR: 2.32; 95% CI: 1.55-3.49; P < 0.001). Higher week 14 infliximab concentrations were also independently associated with week 54 composite remission (OR: 2.05; 95% CI: 1.10-3.82; P = 0.023). Based on receiver operating characteristic curve analysis, week 14 infliximab concentrations thresholds with combined maximal sensitivity and specificity of ≥20.2 µg/mL at week 2, ≥15 µg/mL at week 6, and ≥7.2 µg/mL at week 14 were associated with week 14 composite remission. DISCUSSION: Higher post-induction infliximab concentrations are associated with early and long-term favorable therapeutic outcomes in patients with fistulizing CD.

[A Case of Enterocutaneous Fistula Caused by Cytomegalovirus Enteritis after Gastrectomy Successfully Treated with Antiviral Therapy-A Case Report].

Cytomegalovirus(CMV)infection is a well-recognized complication of immunodeficiency. We present the case of a 90- year-old female admitted due to gastric cancer. Fifty-seven days after gastrectomy, intestinal juice was observed from the umbilical wound, which was suspected of anastomotic failure or gastrointestinal perforation. Abdominal computed tomography didn't reveal gastrointestinal perforation. CMV enteritis was diagnosed by transanal double-balloon endoscopy from the cecum to the oral side 15 cm of the ileum. Enterocutaneous fistula was considered to be caused by CMV enteritis. The intestinal fluid outflow from the wound disappeared treated with ganciclovir, and the ulcer in the intestinal tract disappeared, too. We report this case to reinforce the importance of considering CMV infection as a differential diagnosis in gastrointestinal perforation of compromised patients.

The role of topical therapy for perianal fistulizing Crohn's disease: are we forgetting something?

INTRODUCTION: Rectal inflammation is the principal risk factor for the development of perianal fistulizing Crohn's disease. However, no topical therapy direct to rectal healing is discussed in European' guidelines. The aim of this systematic review was to evaluate the role of topical therapy in healing the rectal inflammation in Crohn's disease. EVIDENCE ACQUISITION: A MEDLINE search of all studies published in English until December 2018 was conducted. Articles were identified using the strings "Crohn's disease and topical therapy" or "perianal Crohn's disease and topical therapy." EVIDENCE SYNTHESIS: Contradictory results about the efficacy of topical metronidazole were present. No benefit from topical tacrolimus use was demonstrated. Mesalazine suppositories induced and maintained remission of rectal inflammation in 50% of patients with rectal Crohn's disease. Few data were available about the role of local therapy for the fistulous tract in Crohn's disease. Local mesenchymal stem cells therapy could be a promising new approach. CONCLUSIONS: Due to the disappoint success rate of current strategy in perianal fistulizing Crohn's disease, the role of rectal inflammation as a causative factor and the fair success rate of topical therapy with mesalazine suppositories in the healing of rectal inflammation without relevant side effects, more studies are advisable in this field.

Anti-tumor necrosis factor agents in Crohn's disease and ulcerative colitis: Beyond luminal disease. / Agentes anti-factor de necrosis tumoral en enfermedad de Crohn y colitis ulcerosa: más allá de la enfermedad luminal.

Anti-tumor necrosis factor agents (anti-TNF) drugs are commonly used in patients with inflammatory bowel disease (IBD) and have proven effective in both induction and maintenance therapy in luminal Crohn's disease and ulcerative colitis. Their efficacy has also been proven in fistulising perianal Crohn's disease. However, the evidence in other scenarios, such as stricturing, penetrating and non-fistulising perianal Crohn's disease, extraintestinal IBD manifestations and ileoanal reservoir complications, is not as robust. The aim of this review was to perform an analysis of the available literature and to determine the role of anti-TNF drugs in common clinical practice in patients affected by these complications.

Efficacy of Vedolizumab in Fistulising Crohn's Disease: Exploratory Analyses of Data from GEMINI 2.

BACKGROUND AND AIMS: Medical management of fistulising Crohn's disease [CD] is constrained by the limited number of available therapies. We evaluated the efficacy of vedolizumab, a gut-selective α4ß7 integrin antagonist approved for treating moderately to severely active CD, in a subpopulation of patients with fistulising CD who participated in the GEMINI 2 trial [NCT00783692]. METHODS: Exploratory analyses of data from the GEMINI 2 trial were conducted in 461 responders to 6-week vedolizumab induction therapy who received maintenance placebo [VDZ/PBO, N = 153] or vedolizumab [VDZ/VDZ, N = 308]. Fistula closure rates were assessed at Weeks 14 and 52, and the time to fistula closure was analysed by the Cox proportional hazards model with adjustments for significant covariates. RESULTS: At entry into the maintenance period, 153 [33%] patients had a history of fistulising disease and 57 [12%] patients had ≥1 active draining fistula. By Week 14, 28% of VDZ/VDZ-treated patients compared with 11% of VDZ/PBO-treated patients (95% confidence interval [CI], -11.4 to 43.9) achieved fistula closure. Corresponding rates at Week 52 were 31% and 11% (absolute risk reduction [ARR]: 19.7%; 95% CI, -8.9 to 46.2). Similarly, VDZ/VDZ-treated patients had faster time to fistula closure and were more likely to have fistula closure at Week 52 [33% vs 11%; HR: 2.54; 95% CI, 0.54-11.96]. Prior failure of antibiotic therapy was a negative predictor of fistula closure [HR: 0.217; 95% CI, 0.059-0.795; p = 0.021], whereas trough vedolizumab concentrations did not affect closure rates. CONCLUSIONS: Our findings are consistent with the beneficial effect of vedolizumab treatment for fistulising CD.

Use of Anti-Tumor Necrosis Factors and Anti-Integrins in the Treatment of Crohn's Disease.

In patients with Crohn's disease (CD), anti-tumor necrosis factor (TNF) therapy is efficacious for the induction and maintenance of clinical remission, mucosal healing, reducing rates of surgery and hospitalizations, and improving health-related quality of life. The decision between anti-TNFs and anti-integrins as first-line treatment in CD depends on disease severity, safety concerns, and prescription coverage. Given the existing data on long-term outcomes and safety, anti-TNFs are often preferred to anti-integrins. Additional clinical experience and preferably prospective, head-to-head studies will be important to determine whether vedolizumab should be considered more often for first-line therapy in CD.

Unusual case of duodenobiliary fistula complicating Crohn's disease successfully treated with Adalimumab.

Crohn's disease (CD) is characterized by transmural inflammation of the gastrointestinal tract, which predisposes to the formation of fistula. Duodenal involvement occurs in less than 5% of cases and often leads to clinically relevant strictures. However, fistula formation in the duodenum is exceptional. Herein, we report an unusual case of duodenobiliary fistula due to CD occurring in a 65-year-old patient who was successfully treated by anti-tumor necrosis factor (TNF) agents. This case report highlights the efficacy of anti-TNF alpha agents in the treatment of a bilioenteric fistula because it increases the probability of clinical remission and mucosal healing and therefore reduces the need for surgical treatment which may be associated morbidity.

Stable gastric pentadecapeptide BPC 157 heals rat colovesical fistula.

To establish the effects of BPC 157 on the healing of rat colovesical fistulas, Wistar Albino male rats were randomly assigned to different groups. BPC 157, a stable gastric pentadecapeptide, has been used in clinical applications-specifically, in ulcerative colitis-and was successful in treating both external and internal fistulas. BPC 157 was provided daily, perorally, in drinking water (10µg/kg, 12ml/rat/day) until sacrifice or, alternatively, 10µg/kg or 10ng/kg intraperitoneally, with the first application at 30min after surgery and the last at 24h before sacrifice. Controls simultaneously received an equivolume of saline (5.0ml/kg ip) or water only (12ml/rat/day). Assessment (i.e., colon and vesical defects, fistula leaking, fecaluria and defecation through the fistula, adhesions and intestinal obstruction as healing processes) took place on days 7, 14 and 28. Control colovesical fistulas regularly exhibited poor healing, with both of the defects persisting; continuous fistula leakage; fecaluria and defecation through the fistula; advanced adhesion formation; and intestinal obstruction. By contrast, BPC 157 given perorally or intraperitoneally and in µg- and ng-regimens rapidly improved the whole presentation, with both colon and vesical defects simultaneously ameliorated and eventually healed. The maximal instilled volume was continuously raised until it reached the values of healthy rats, there were no signs of fecaluria and no defecation through the fistula, there was counteraction of advanced adhesion formation or there was an intestinal obstruction. In conclusion, BPC 157 effects appear to be suited to inducing full healing of colocutaneous fistulas in rats.

Outcomes of Medical and Surgical Therapy for Entero-urinary Fistulas in Crohn's Disease.

BACKGROUND AND AIMS: The aims of this study were to evaluate the frequency of entero-urinary fistulas in a cohort of Crohn's disease (CD) patients and to analyse the outcomes of medical and surgical therapy. METHODS: This multicentre retrospective study included all CD patients with entero-urinary fistulas diagnosed by the presence of clinical symptoms and confirmed at surgery or by radiological or endoscopic techniques. We evaluated outcomes of medical and surgical therapy. We defined remission as absence of clinical symptoms with a radiological confirmation of fistula closure. Cox regression analysis was performed to evaluate factors predictive of achieving remission without need for surgery. RESULTS: Of 6081 CD patients screened, 97 had entero-urinary fistulas (frequency 1.6%). Seventy-five percent of fistulas occurred in men. After a median follow-up of 91 months, 96% of patients were in sustained remission. Thirty-three patients (35%) received anti-tumour necrosis factor (TNF) therapy. Of these, 45% achieved sustained remission (median follow-up 35 months) without needing surgery. More than 80% of patients required surgery, which induced remission (median follow-up 101 months) in 99% of them. Only the use of anti-TNF agents was associated with an increased rate of remission without need for surgery (hazard ratio 0.23, 95% confidence interval 0.12-0.44; p < 0.001). CONCLUSION: In this large cohort of CD patients, the frequency of entero-urinary fistulas was lower than previously described. More than 80% of patients required surgery, and in all but one of them surgery induced sustained remission. In a selected subgroup of patients, anti-TNF may induce long-term fistula remission and radiographic closure, making it possible to avoid surgery.

Clinical experience of the use of adalimumab in the management of hidradenitis suppurativa. Comparison of response rates with Crohn disease. / Experiencia clínica del uso de adalimumab en el manejo de la hidradenitis supurativa. Comparando las tasas de respuesta con la enfermedad de Crohn.

The recent approval of adalimumab as the first treatment to be approved for the management of hidradenitis suppurativa has represented a before and after in the control of this chronic inflammatory disease. Given the inflammatory burden of this cutaneous disease, in the last few years hidradenitis suppurativa has been compared with inflammatory bowel disease, particularly with Crohn disease, to the point of considering hidradenitis suppurativa as "Crohn disease of the skin". These two chronic inflammatory diseases show sufficient similarities to consider whether treatment response based on the inflammatory load could also be similar. The present article aims to analyse the efficacy of adalimumab in hidradenitis suppurativa in comparison with a truly comparable disease, Crohn disease, with a view to evaluating therapeutic response rates and to drawing conclusions on the therapeutic success obtained in this disabling cutaneous disease.

Effect of adalimumab on an enterocutaneous fistula in patients with Crohn's disease: a case series.

Crohn's disease (CD) is characterized by transmural inflammation of the gastrointestinal tract, which predisposes patients to the formation of a fistula. The efficacy of adalimumab (ADA) for an enterocutaneous fistula remains unclear. In this report, we present a case series of 3 patients with enterocutaneous fistulizing CD treated with ADA. ADA treatment achieved sustained complete fistula closure in one patient. The other two cases, which failed to achieve fistula closure, had intestinal stenosis and were not receiving concomitant azathioprine. Combination therapy with ADA and azathioprine may be a useful option and an alternative to surgery for enterocutaneous fistulizing CD.

Colovesical fistula presenting as Listeria monocytogenes bacteraemia.

We present a case of colovesical fistula presenting with a clinical syndrome of urosepsis subsequently demonstrated to be due to Listeria monocytogenes bacteraemia. The patient had a history of previous rectal cancer with a low anterior resection and a covering ileostomy that had been reversed 6 months prior to this presentation. L. monocytogenes was also isolated among mixed enteric organisms on urine culture. There were no symptoms or signs of acute gastrointestinal listeriosis or meningoencephalitis. This unusual scenario prompted concern regarding the possibility of communication between bowel and bladder, which was subsequently confirmed with CT and a contrast enema. The patient recovered well with intravenous amoxicillin and to date has declined surgical management of his colovesical fistula. This case illustrates the importance of considering bowel pathology when enteric organisms such as Listeria are isolated from unusual sites.

Double pylorus in a patient with Behçet's syndrome.

We report a patient with Behçet's syndrome who presented with upper gastrointestinal haemorrhage. Gastroduodenoscopy showed a gastroduodenal fistula which caused the appearance of double pylorus in the antrum. The possibility of peptic ulcer disease related to non-steroidal anti-inflammatory drug use or Behçet's syndrome itself, as the cause of this rare condition in this patient is discussed.