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).

Severe hyperglycemia following transition from octreotide to lanreotide in a patient with enterocutaneous fistula receiving parenteral nutrition.

Somatostatin analogues, suchas octreotide and lanreotide, are commonly used in the management of enterocutaneous fistula. We report a case of severe and prolonged hyperglycemia that occurred in a patient after receiving a one-time dose of lanreotide, who had previously been stable on octreotide and did not have a history of diabetes mellitus. Management of the patient's hyperglycemia while receiving parenteral nutrition is described.

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.

Topical Management of Enterocutaneous and Enteroatmospheric Fistulas: A Systematic Review.

Enterocutaneous (ECF) and enteroatmospheric (EAF) fistulas are associated with considerable morbidity and patient care challenges, including optimal topical management. PURPOSE: A systematic literature review was conducted to identify topical management interventions used in ECF/EAF care and to explore the role of these interventions in fistula closure and long-term fistula management. METHODS: A search of PubMed, the Cumulative Index of Nursing and Allied Health Literature, and Scopus was conducted to identify English-language articles published from January 2004 to January 2019. The keywords enterocutaneous fistula, enteroatmospheric fistula, negative pressure wound therapy, NPWT, vacuum-assisted closure, VAC, pouch or pouching, troughing, bridging, collection device, dressing, and wound care were used to identify all publications pertaining to the topical management of adult and mixed adult/pediatric patients with an ECF or EAF. Single-person case studies, exclusively pediatric studies, surgical treatment-based, and duplicate publications were excluded. Abstracts were screened for relevance to the research questions, and eligible publications were abstracted and categorized using The Oxford Centre for Evidence-Based Medicine Levels of Evidence. The Joanna Briggs Institute (JBI) critical appraisal checklist for case series was used to assess each article for risk of bias and methodological quality. Outcomes of interest included patient demographics, closure rates, fistula classification (type of fistula, fistula output, fistula origin), type of topical treatment, adverse events (pain, new fistula formation, fistula recurrence, mortality), follow-up, long-term management, perifistula skin protection, effluent management, dressing change frequency, and quality of life. Descriptive statistics were presented; no statistical analysis was performed. RESULTS: Of the 983 articles identified, 57 underwent critical appraisal using the JBI checklist for case series. Forty-two (42) did not meet the inclusion criteria, leaving 15, level IV, case-based publications (N = 410 patients). No randomized controlled trials were found. All studies included some form of negative pressure wound therapy. JBI results found that each study was at high risk of bias in more than 2 domains. Interventions were categorized as intubation, occlusion, or isolation of the fistula. Of the 559 fistulas treated, spontaneous closure was reported in 164 cases, with rates ranging from 0% to 100%. Adverse events to treatment included pain (n = 33 patients), new fistula formation (n = 12), and fistula recurrence (n = 1). Sepsis was the leading cause of mortality (n = 29), with reported rates ranging from 0% to 44%. CONCLUSION: Due to the high risk of study bias and low quality of evidence, the exact contribution of any one intervention could not be established. Results also suggest a high risk of publication bias, and patient-centered outcomes were reported in only 1 study. Although topical management might play a role in fistula closure, it is only as part of a comprehensive plan of care. Future research should focus on developing and using standardized reporting tools, classifications, and outcomes and include patient-centered outcomes such as acceptance, tolerability, pain, and quality of life relating to any one intervention. At this time, the evidence base for management recommendations is limited, suggesting that interventions should mainly be based on practical considerations such as resources and clinician skill.

[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.

An obscure case of using apixaban anti-Xa levels in a morbidly obese patient who was nil per os with enterocutaneous fistula.

: Apixaban anti-Xa levels have been introduced to monitor apixaban activity. Presented is a fundamental use of anti-Xa monitoring in questionable absorption in enterocutaneous fistula. A 57-year-old morbidly obese male (150 kg, BMI 42.5) presented to the emergency department with deep venous thromboses and pulmonary embolisms. He also had high-output enterocutaneous fistula managed with an abdominal collection device, total parental nutrition therapy, and nil per os status. He was able to take some oral (PO) medications; however, he reported finding whole capsules in his collection device. He refused enoxaparin injections for venous thromboembolism treatment. The decision was made to load with apixaban therapy with anti-Xa monitoring. After two 10-mg doses, peak apixaban anti-Xa level was 146 ng/ml which fell within on-therapy levels in the AMPLIFY study, prothrombin time 18 s, partial thromboplastin time 35.5 s, international normalized ration 1.5. Monitoring was an important factor in this patient with questionable absorption and further complicated by his morbid obesity which has not been adequately studied in clinical trials.

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.

The use of the somatostatin analogue octreotide for the conservative management of symptomatic cholecystocolonic fistula: a case report.

An 84-year-old woman presented with acute worsening of diarrhoea for a few weeks, with a background of chronic diarrhoea over the past 12 months accompanied by weight loss. Computed tomography during this admission revealed air in the biliary tree and resolution of gallstones in keeping with a cholecystocolonic fistula. Owing to her comorbidities, surgical management was deemed not to be the best option. She was trialled on octreotide, a somatostatin analogue, which effectively resolved her symptoms. This case presents an effective and novel method of managing cholecystocolonic fistulas conservatively in a patient where medical therapy is the ceiling of care.

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.

Octreotide and enterocutaneous fistula closure in neonates and children.

UNLABELLED: Enterocutaneous fistula and its conservative management still pose a challenge for the surgeon. The use of octreotide and somatostatin in neonates and children as adjunctive therapy in the conservative management of this condition, leads to major controversy regarding its efficacy. Therefore, we conducted an extensive literature review of published articles regarding the use of somatostatin and its analogues in the treatment of enterocutaneous fistula in neonates and children. Our review is then presented together with a case vignette and discusses the different practical aspects of the treatment with these drugs. CONCLUSION: The major diversity in treatment regimens among published studies makes outcomes difficult to compare. However, given the results of the different cases reported in the literature and of our own experience, we suggest a possible beneficial effect of octreotide and somatostatin on closure of enterocutaneous fistula in these patients.

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.