Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis.

OBJECTIVE: In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B5, a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury. DESIGN: We performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives. RESULTS: VNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD. CONCLUSION: The induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B5-driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy.

Efficacy and Safety of Infliximab Retreatment in Crohn's Disease: A Multicentre, Prospective, Observational Cohort (REGAIN) Study from the GETAID.

INTRODUCTION: The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance. METHODS: We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Index >150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index of <150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic. RESULTS: At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%, P = 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26. DISCUSSION: In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions.

Three-year outcome of local injection of autologous stromal vascular fraction cells and microfat in refractory perianal fistulas of Crohn's disease.

Perianal fistulas in Crohn's disease are frequent and disabling, with a major impact on patients' quality of life. Cell-based therapy using mesenchymal stem cells represents new hope for these patients, but long-term efficacy remains challenging. In a pilot study, including patients with refractory complex perianal fistulas, autologous adipose-derived stromal vascular fraction (ADSVF) combined with microfat achieved combined remission in 60% of cases, with a good safety profile at 1 year. The purpose of this study is to assess whether these results were maintained at longer term. The safety and efficacy data of the ten patients were evaluated retrospectively 3 years after injection on the basis of clinical and radiological data. MRI were analysed according to the MAGNIFI-CD score. No adverse event was attributed to the experimental stem-cell treatment. Combined remission was achieved in 7 patients (70%) and associated with a significant improvement in the MAGNIFI-CD MRI score. In conclusion, the safety and efficacy of ADSVF and microfat injection in Crohn's disease fistulas were maintained at 3 years, demonstrating that this innovative strategy is effective in producing a long-lasting healing effect. The ongoing multicentre randomized placebo-controlled trial (NCT04010526) will be helpful to define the place for this approach in the current therapeutic arsenal.

Impact of Gastric Electrical Stimulation on Economic Burden of Refractory Vomiting: A French Nationwide Multicentre Study.

BACKGROUND & AIMS: Medico-economic data of patients suffering from chronic nausea and vomiting are lacking. In these patients, gastric electrical stimulation (GES) is an effective, but costly treatment. The aim of this study was to assess the efficacy, safety and medico-economic impact of Enterra therapy in patients with chronic medically refractory nausea and vomiting. METHODS: Data were collected prospectively from patients with medically refractory nausea and/or vomiting, implanted with an Enterra device and followed for two years. Gastrointestinal quality of life index (GIQLI) score, vomiting frequency, nutritional status and safety were evaluated. Direct and indirect expenditure data were prospectively collected in diaries. RESULTS: Complete clinical data were available for142 patients (60 diabetic, 82 non-diabetic) and medico-economic data were available for 96 patients (36 diabetic, 60 non-diabetic), 24 months after implantation. GIQLI score increased by 12.1 ± 25.0 points (p < .001), with a more significant improvement in non-diabetic than in diabetic patients (+15.8 ± 25.0 points, p < .001 versus 7.3 ± 24.5 points, p = .027, respectively). The proportion of patients vomiting less than once per month increased by 25.5% (p < .001). Hospitalisations, time off work and transport were the main sources of costs. Enterra therapy decreased mean overall healthcare costs from 8873 US$ to 5525 US$ /patient/year (p = .001), representing a saving of 3348 US$ per patient and per year. Savings were greater for diabetic patients (4096 US$ /patient/year) than for non-diabetic patients (2900 US$ /patient/year). CONCLUSIONS: Enterra therapy is an effective, safe and cost-effective option for patients with refractory nausea and vomiting. CLINICALTRIALS: gov Identifier: NCT00903799.

Endoscopic mucosal resection of sporadic duodenal nonampullary adenoma: outcomes of 130 patients with a long-term follow up in two tertiary French centers.

BACKGROUND: The long-term outcomes and safety of endoscopic mucosal resection (EMR) of sporadic duodenal adenoma (SDA), and the management of adverse events need to be confirmed. METHODS: A bicentric retrospective study was performed including all patients who underwent EMR for SDAs from 2003-2016. The primary aim was to evaluate the efficiency of EMR for SDA. The secondary objectives were to assess safety, recurrence management, predictive factors for treatment success, and adverse events. RESULTS: One hundred thirty patients (134 procedures) were included (median age 65 years, 49.3% male). The mean SDA size was 20.7 (range 5-50) mm. Of the SDAs, 58.2% were category 3 of the Vienna classification, 35.8% were category 4, and 5.9% were category 5. The median follow up was 25.0 (range 2-120) months. Complete mucosal resection was achieved for 129/134 lesions (96.2%), with en bloc resection in 59/134 (44%). Recurrence occurred in 28.6% of cases (30/105 procedures). Recurrence was successfully treated by new endoscopic procedures in 72.2% (13/18) and by surgery in 27.8% (5/18). Delayed bleeding occurred in 13.4% of cases (18/134) and was successfully managed endoscopically. The perforation rate was 3.7% (5/134); perforations were managed without surgery in 60% (3/5 patients) of cases. CONCLUSIONS: Endoscopic treatment of SDA appears to be effective and relatively safe in tertiary centers. All bleeding complications were endoscopically controlled, and perforation was rare. Recurrence was frequent but could be managed endoscopically. EMR is confirmed as a first-line treatment in cases of SDA, and surgery is useful only if repeated EMRs fail.

Cuffitis: is an endoscopic approach possible?

Background Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the reference surgical treatment for patients with ulcerative colitis (UC) refractory to medical treatment. One of the complications is leaving a strip of rectal mucosa which can be a cause of persistent inflammation or cuffitis. The objective of our study is to present an endoscopic approach for the treatment of cuffitis. Methods This retrospective study included three patients who suffered from cuffitis after a proctocolectomy with IPAA for UC refractory to medical treatment. An endoscopic resection of the cuffitis was performed by the same operator. Two different techniques were used: hybrid endoscopic submucosal dissection (ESD) for one patient and mucosectomy with cap and resection for the two others. Results The endoscopic treatment was performed successfully in all three patients. The only complication observed was rectal bleeding which did not require endoscopic revision. The three patients are now asymptomatic. Conclusion Endoscopic treatment of cuffitis appears to be an interesting approach with few complications in the short term and good clinical efficacy.

Monitoring of infliximab trough levels and anti-infliximab antibodies in inflammatory bowel diseases: A comparison of three commercially available ELISA kits.

BACKGROUND: There are many studies presenting data of biologics and several ELISA kits commercially available for monitoring infliximab serum trough levels (s-IFXt) and anti-drug antibodies (ADAb). We propose to compare technical characteristics and results of three different assays on a cohort of 35 patients under infliximab (IFX) and suffering from inflammatory bowel disease (IBD). PATIENTS AND METHODS: s-IFXt and ADAb were systematically measured with three ELISA kits: Lisa-Tracker® Duo infliximab (Theradiag®), Ridascreen® IFX Monitoring (R-Biopharm AG®) and Promonitor® IFX (Progenika Biopharma SA®). RESULTS: The main technical features that differed between kits for measuring s-IFXt were: (i) TNF coating, (ii) immune complexes revelation strategy and/or (iii) interference with other anti-TNFα agents. For kits measuring ADAb, they were revelation steps and unit of results. There was an excellent mathematical correlation of s-IFXt between assays however Bland-Altman analysis denoted (i) s-IFXt were on average 48 to 69% higher in Ridascreen® than in the other two assays, and (ii) elevated s-IFXt were higher with Promonitor® compared to Lisa-Tracker®. As a consequence, there were some substantial discrepancies between assays for classification of s-IFXt into concentration ranges. Despite unstandardized units, pairwise qualitative comparison showed a perfect agreement between the three pairs of ADAb assays. CONCLUSION: Our data show that the evaluated assays are not quantitatively interchangeable due to substantial variations in some results that could lead, for some patients, to divergent therapeutic decisions. We remind to be cautious when comparing study results issued from different kits and recommend using the same assay for the longitudinal follow-up of IBD patients.

Gastric Electrical Stimulation Reduces Refractory Vomiting in a Randomized Crossover Trial.

BACKGROUND & AIMS: There have been conflicting results from trials of gastric electrical stimulation (GES) for treatment of refractory vomiting, associated or not with gastroparesis. We performed a large, multicenter, randomized, double-blind trial with crossover to study the efficacy of GES in patients with refractory vomiting, with or without gastroparesis. METHODS: For 4 months, we assessed symptoms in 172 patients (66% women; mean age ± standard deviation, 45 ± 12 years; 133 with gastroparesis) with chronic (>12 months) of refractory vomiting (idiopathic, associated with a type 1 or 2 diabetes, or postsurgical). A GES device was implanted and left unactivated until patients were randomly assigned, in a double-blind manner, to groups that received 4 months of stimulation parameters (14 Hz, 5 mA, pulses of 330 µs) or no stimulation (control); 149 patients then crossed over to the other group for 4 months. Patients were examined at the end of each 4-month period (at 5 and 9 months after implantation). Primary endpoints were vomiting score, ranging from 0 (daily vomiting) to 4 (no vomiting), and the quality of life, assessed by the Gastrointestinal Quality of Life Index scoring system. Secondary endpoints were changes in other digestive symptoms, nutritional status, gastric emptying, and control of diabetes. RESULTS: During both phases of the crossover study, vomiting scores were higher in the group with the device on (median score, 2) than the control group (median score, 1; P < .001), in diabetic and nondiabetic patients. Vomiting scores increased significantly when the device was ON in patients with delayed (P < .01) or normal gastric emptying (P = .05). Gastric emptying was not accelerated during the ON period compared with the OFF period. Having the GES turned on was not associated with increased quality of life. CONCLUSIONS: In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life. Clinicaltrials.gov, Number: NCT00903799.

Esophageal Motor Disorders Are a Strong and Independant Associated Factor of Barrett's Esophagus.

BACKGROUND/AIMS: Esophageal motor disorder (EMD) has been shown to be associated with gastroesophageal reflux disease (GERD). However, the association of EMD with a Barrett's esophagus (BE) is controversial. Our objective was to evaluate whether the presence of EMD was an independent factor associated with BE. METHODS: A retrospective case-control study was conducted in GERD patients who all had oeso-gastroduodenal endoscopy and high-resolution esophageal manometry. The clinical data collected was known or potential risk factors for BE: male gender, smoking and alcohol consumption, age, body mass index, presence of hiatal hernia, frequency, and age of GERD. EMD were classified according to the Chicago classification into: ineffective motor syndrome, fragmented peristalsis and absence of peristalsis, lower esophageal sphincter hypotonia. RESULTS: Two hundred and one patients (101 in the GERD + BE group and 100 in the GERD without BE) were included. In univariate analysis, male gender, alcohol consumption, presence of hiatal hernia, and EMD appeared to be associated with the presence of BE. In a multivariate analysis, 3 independent factors were identified: the presence of EMD (odds ratio [OR], 3.99; 95% confidence interval [CI], 1.71-9.28; P = 0.001), the presence of hiatal hernia (OR, 5.60; 95% CI, 2.45-12.76; P ＜ 0.001), Helicobacter pylori infection (OR, 0.08; 95% CI, 0.01-0.84; P = 0.035). CONCLUSIONS: The presence of EMD (particularly ineffective motor syndrome and lower esophageal sphincter hypotonia) is a strong independent associated factor of BE. Searching systematically for an EMD in patients suffering from GERD could be a new strategy to organize the endoscopic follow-up.

Granulocyte/monocyte adsorptive apheresis for the treatment of therapy-refractory chronic active ulcerative colitis.

OBJECTIVES: Current options for patients with steroid-dependent, chronic-active ulcerative colitis (UC) with insufficient response/intolerance to immunosuppressants (ISs) and/or biologics are limited. The aim of this study was to assess the long-term outcome of granulocyte/monocyte adsorptive (GMA) apheresis (Adacolumn®) in this population. MATERIALS AND METHODS: Ninety five adults with steroid-dependent active UC and insufficient response/intolerance to IS and/or TNF inhibitors received 5-8 aphereses in a single induction series of ≤10 weeks. Endpoints included rates of remission (clinical activity index [CAI] ≤ 4) at weeks 24 and 48. RESULTS: Of 94 patients (ITT population), remission and response rates were 34.0% and 44.7% at week 24, and 33.0% and 39.4% at week 48. Among 30 patients with prior failure of IS and biologics, 33.3% and 20.0% were in remission at weeks 24 and 48. At both weeks, 19.2% of patients achieved steroid-free remission. Sustained remission or response occurred in 27.7% of patients at 48 weeks. The cumulative colectomy rate at week 96 was 23.4%. Safety was consistent with previous findings. CONCLUSIONS: This study confirms findings of the 12-week interim analysis and demonstrates that GMA apheresis provides a safe and beneficial long-term outcome for patients with chronic active UC resistant/intolerant to IS and/or TNF inhibitors.

First clinical case report of local microinjection of autologous fat and adipose-derived stromal vascular fraction for perianal fistula in Crohn's disease.

Mesenchymal stem cell therapy is a promising treatment for perianal Crohn's fistulas refractory to conventional therapy, which are an extremely morbid complication and a true therapeutic challenge. Autologous adipose-derived stromal vascular fraction (ADSVF) is an easily accessible source of cells with angiogenic, anti-inflammatory, immunomodulatory, and regenerative properties. Here, we describe a case involving a patient with severe perianal Crohn's fistulas refractory to the best medical and surgical practices who received local treatment with ADSVF and microfat. This patient was first examined under anesthesia with drainage via seton placement; 1 week later, on a single day, he underwent adipose tissue extraction, ADSVF and microfat preparation, and the local injection of 14 ml of microfat and approximately 20 million viable ADSVF cells into the soft tissue around the fistulas. No serious adverse events were observed. At the first endpoint at 12 weeks, the fistula had clinically healed with complete re-epithelialization of all external openings; no fistula tract was detected on magnetic resonance imaging, confirming this finding. This good clinical outcome was sustained at 48 weeks and was associated with a reduction in the severity of perianal disease and an improvement in quality of life. The current case highlights the therapeutic potential of a new cellular treatment for Crohn's patients with refractory perianal fistulas based on the innovative hypothesis that the combined action of ADSVF in association with the trophic characteristics of a microfat graft could be beneficial for this condition. TRIAL REGISTRATION: EudraCT number 201325, NCT02520843 . Registered on 5 August 2015.

Endoscopic perforations: what are the indications for surgery?

BACKGROUND: Despite their low occurrence, endoscopic perforations (EPs) are concerning. Some predictive factors have been identified, and EP management is debated, whether non-surgical (medical and/or endoscopic) or surgical. The objective was to elaborate a predictive score for surgical management of EP. METHODS: All the patients addressed for upper and lower EP, except oesophageal EP, were retrospectively included (2004-2015). Demographic data, endoscopic features (indication, location, type), clinical, biological and radiological presentations of EP were reviewed. Management of EP and outcomes were recorded. A predictive score was constructed by multiple linear regression and a cut-off value for surgical management was identified. Additional subgroup analysis was performed according to the location of EP (upper and lower). RESULTS: Among 41150 endoscopic procedures, 44 patients (22 males, median age = 65 years [22-87]) presenting with EP were included (0.09%). Lower gastrointestinal (GI) endoscopy was mostly performed (66%). EP diagnosis was immediate in 73% of the cases (n = 32). Non-surgical management was efficient in 2/3 cases treated medically alone, and 18/20 cases treated by endoscopy. Surgical management was always successful (n = 24/24). In case of peritonitis, surgery was systematically required, whereas easily required in case of delayed diagnostic of EP. The EP score was based on the presence of previous abdominal surgery, lower GI endoscopy and diagnostic endoscopy. A cut-off EP score of 22.8% for surgery was chosen; it was associated with a specificity and sensitivity of 40 and 100%, respectively. When subgroups were analysed according to EP location, the EP score was still based on the presence of previous abdominal surgery and diagnostic endoscopy. The cut-off was 6.3 and 73.3% for upper (specificity: 73%, sensitivity: 100%) and lower (89 and 45%) locations, respectively. CONCLUSION: The predictive EP score may avoid inappropriate surgical management, as well as delayed surgery after non-surgical management failure. Forthcoming study should prospectively validate this score.

Does faecal diversion prevent morbidity after ileocecal resection for Crohn's disease? Retrospective series of 80 cases.

BACKGROUND: After ileocecal resection for Crohn's disease, a temporary faecal diversion is indicated in high-risk patients. The impact of a temporary stoma on post-operative morbidity has been poorly assessed so far. The aim was to analyse post-operative morbidity of temporary faecal diversion after ileocecal resection for Crohn's disease. METHODS: Patients undergoing temporary faecal diversion combined with ileocecal resection were retrospectively included. Patients presenting with complications were compared with patients with an uneventful post-operative course, to identify any predictive factor for morbidity. RESULTS: Eighty faecal diversions were performed (43 males, 33.5 (18-75) years), including 63 split stoma (79%) and 17 covering loop ileostomies (21%). Fifty-two patients (65%) presented with a perforating disease. Post-operative complications occurred in 15 patients (19%), 15 days after surgery (1-30). The main complications were intra-abdominal abscess (n = 6), functional renal failure (n = 6), fistula (n = 2) and stomal prolapse (n = 2). Two patients required surgery. Previous bowel resections (60% versus 28%, P = 0.01) were significantly associated with post-operative morbidity. CONCLUSIONS: Temporary faecal diversion is useful in high-risk patients after ileocecal resection for Crohn's disease. Patients' information about post-operative risks remains an important issue. Risk factors for post-operative morbidity despite faecal diversion are previous bowel resections.

Gastric per-oral endoscopic myotomy with antropyloromyotomy in the treatment of refractory gastroparesis: clinical experience with follow-up and scintigraphic evaluation (with video).

BACKGROUND AND AIMS: Gastroparesis is a chronic, debilitating condition. We report an experience conducting gastric per-oral endoscopic pyloromyotomy (G-POEM) with objectives to assess clinical efficacy, gastric emptying evolution, and procedural adverse events. METHODS: This was a clinical pilot series on 12 consecutive patients who underwent G-POEM for refractory gastroparesis in our tertiary center between February 2014 and August 2015. Patients included had severe disease as defined by elevated Gastroparesis Cardinal Symptoms Index (GCSI) score and delayed gastric emptying scintigraphy (GES). G-POEM was performed by mucosal incision upstream the pylorus followed by submucosal tunnel and antropyloromyotomy with subsequent access closure. Efficacy was assessed at 5 days, 1 month, and 3 months, based on GCSI score, and individualizing (Likert scale) the main symptoms (nausea, vomiting, abdominal pain, early satiety, and anorexia). GES was performed 2 months after the procedure. RESULTS: G-POEM was successfully performed in all 12 patients, yielding a technical success rate of 100%. Significant improvements in GCSI were observed: 3.5 ± .8 versus .9 ± .9 (1 month) and 1.1 ± 1.5 (3 months), respectively (P < .001), as well as the severity of main symptoms at 3 months. Clinical efficacy was 85% (10/12). GES normalized in 75% of cases, with improvement of half emptying time (222 ± 90 minutes vs 133 ± 90 minutes; P = .03) and retention at 2 hours (76% ± 20% vs 44% ± 26%; P = .009). There were no adverse events related to the procedure. CONCLUSION: We report a single-center study evaluating G-POEM for refractory gastroparesis, demonstrating its feasibility, reproducibility, and safety with promising clinical and scintigraphic efficacy.

Impacted and Fractured Biliary Basket: A Second Basket Rescue Technique.

A 59-year-old woman was treated with ERCP, ES, and biliary plastic stent, for large and multiple common bile duct stones. During a second ERCP basket extraction was impacted with a round entrapped stone. The basket handle was cut off; a metal sheath of extraendoscopic lithotriptor was advanced over the basket. The mechanical lithotripsy was complicated with basket traction wires fracturing, without breakage of the stone. A rescue standard basket was pushed until it caught the basket/stone complex. Using this method disengagement of the whole fractured basket/stone complex was achieved without need of surgery. It is the third case reported in the English literature.

Esophageal and anorectal involvement in systemic sclerosis: a systematic assessment with high resolution manometry.

OBJECTIVES: In systemic sclerosis (SSc), esophageal and anorectal involvements are frequent and often associated with each other. In clinical practice, esophageal explorations are often prescribed, while anorectal explorations are rarely proposed and therefore, under-recognised. However, it is well documented in the literature that early detection of anorectal dysfunction could delay and/or prevent the onset of symptoms such as fecal incontinence (FI). The main objective was the systematic evaluation and detection of esophageal and anorectal involvements in SSc patients. METHODS: In this monocentric retrospective study, all patients with SSc addressed in the Department of Functional Digestive Explorations, North Hospital, Marseille for esophageal and anorectal explorations were included. Self-Questionnaires, evaluating the symptoms and quality of life, were filled by patients during their visit. Explorations were performed on the same day: high resolution esophageal manometry (EHRM), 3 Dimensional high resolution anorectal manometry (3DHRARM) and endo anal sonography (EUS). RESULTS: 44 patients (41 women), mean age 59.8±12 years, were included. With regard to the symptoms, 45.5% of patients had gastro-esophageal reflux disease (GERD), 66.9% dysphagia, 65.9% constipation and 77.3% FI. The incidence of esophageal dismotility was 65.9%, anorectal and both upper and lower dysfunction were 43.2%. More than 89% patients with abnormal explorations (EHRM, 3DHRARM or both) were symptomatic. Duration of SSc and altered quality of life was correlated with the severity of digestive involvement. CONCLUSIONS: Anorectal dysfunction appears to be closely linked to esophageal involvement in SSc. Their routine screening is undoubtedly essential to limit the occurrence of severe symptoms such as FI.