Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus.

OBJECTIVE: Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. DESIGN: An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. RESULTS: Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. CONCLUSION: This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

Single-centre empirical analysis of double-balloon enteroscopy in the diagnosis and treatment of small bowel diseases: A retrospective study of 466 cases.

BACKGROUND AND OBJECTIVE: The diagnosis and treatment of small bowel diseases (SBDs) has always been a challenge. The purpose of this study was to evaluate the value of double-balloon enteroscopy (DBE) in the diagnosis and treatment of small bowel diseases. METHOD: The clinical data of 466 patients who underwent double-balloon enteroscopy (DBE) in the Endoscope Center of Gastroenterology Department of the First People's Hospital of Yunnan Province from Jan. 2015 to Dec. 2020 were analysed retrospectively. The factors included age, sex, indications, endoscopic treatment results, pathological results, discharge diagnosis and so on. RESULTS: A total of 370 patients underwent 466 double-balloon enteroscopies, among whom 274 underwent one examination and 96 received two-way examinations (oral and transanal approaches). Abnormalities were detected in 299 cases, with a detection rate of 80.81% (299/370). The common indications were occult gastrointestinal bleeding (OGIB) (30.8%, 114/370) and abdominal pain (28.3%, 105/370). The diagnosis rates were 64.9% and 77.1%, respectively. The common positive findings included nonspecific inflammation/erosion (60 cases), ulcers (34 cases), diverticulum (32 cases), polyps (26 cases) and Crohn's disease (CD) (24 cases). The common tumours were lymphoma(12 cases), adenocarcinoma(11 cases) and stromal tumour(8 cases). Lymphoma was mostly located in the ileum, while stromal tumours and adenocarcinoma were mostly located in the duodenum and jejunum. The main endoscopic intervention measures were haemostasis and polypectomy, including haemostatic clip, argon plasma coagulation (APC), endoscopic mucosal resection (EMR), endoscopic trap resection, endoscopic foreign body extraction and other operations, without serious complications. CONCLUSION: DBE has a high success rate in the diagnosis and treatment of some SBDs, and it is a safe and effective management method.

Superior outcomes with double-balloon enteroscopy for small bowel lesion marking followed by intracorporeal as opposed to extracorporeal resection and reconstruction.

BACKGROUND: Double-balloon enteroscopy (DBE) is used for the diagnosis and therapy of small bowel disease. Endoscopic sampling and marking small bowel lesions destined for surgery permit intracorporeal resection and reconstruction (IRR), thereby facilitating a complete minimally invasive technique. There are limited data that compare outcomes of IRR to conventional extracorporeal resection and reconstruction (ERR). The purpose of this study was to evaluate the surgical outcomes of patients undergoing pre-operative DBE for lesion marking followed by laparoscopic IRR compared to those undergoing ERR. METHODS: A retrospective chart review was performed on patients who underwent DBE followed by small bowel resection from 2006 to 2017 at a single tertiary care medical center. IRR was defined as laparoscopic inspection to identify the lesion (previously marked by DBE or by laparoscopic-assisted DBE) followed by intra-abdominal bowel resection and anastomosis with specimen extraction via minimal extension of a laparoscopic port site. ERR was defined as extracorporeal resection and/or reconstruction performed via a conventional or mini-laparotomy abdominal incision. RESULTS: A total of 82 patients met inclusion criteria and were reviewed. Thirty-two patients (39%) had ERR and 50 patients (61%) had IRR. The most common indications for DBE were small bowel bleeding (76%) and small bowel mass or thickening on prior imaging studies (16%). Successful DBE was higher in the IRR group when compared to the ERR group, but not significantly different (90% vs 75%, p-value 0.07). Patients who underwent IRR had faster bowel function recovery (2 vs 4 days, p < 0.01), shorter time to discharge (3 vs 7 days, p < 0.01), and fewer post-operative complications (10 vs 18; p < 0.01), when compared to the ERR group. CONCLUSION: DBE successfully facilitated laparoscopic small bowel IRR and this approach was associated with faster return of bowel function, shorter recovery time, and decreased morbidity when compared to ERR.

Motorised spiral enteroscopy: first prospective clinical feasibility study.

OBJECTIVE: Currently available methods for small bowel endoscopy are often time consuming; motorised PowerSpiral Enteroscopy (PSE) is a further development of spiral enteroscopy to facilitate the approach to the small bowel. The aim of this bicentric prospective trial was to study feasibility and yield of peroral PSE. DESIGN: Consecutive patients with suspected small bowel disease and indication for antegrade enteroscopy were included in two tertiary referral centres. Primary objective was diagnostic yield of antegrade PSE. Secondary objectives included technical success (defined as successful endoscope insertion at least to ligament of Treitz), depth of maximum insertion (DMI), median insertion time to DMI, rate of therapeutic procedures and adverse events. RESULTS: During a 30-month period, 140 procedures were performed on 132 patients (58 female, 74 male; median age: 68 (20-100) years) under general anaesthesia. Overall diagnostic yield of PSE was 74.2%; with 68.2% of procedures including some form of endotherapy. Technical success rate of PSE was 97%; median DMI was 450 cm (0-600) with a median insertion time to DMI of 25 min (3-122). Antegrade panenteroscopy to the cecum was achieved in 14 cases (10.6%). Overall adverse event (AE) rate was 14.4%; two major serious AEs occurred (1.5%), one delayed perforation, one bleeding from Mallory-Weiss lesion. CONCLUSION: This pilot clinical trial demonstrates that PSE is effective for diagnostic and therapeutic antegrade enteroscopy and may compare favourably with traditional methods of deep enteroscopy in ease of use and procedural duration. More comparative data are required to assess clinical application and safety of PSE. TRIAL REGISTRATION NUMBER: NCT02965209.

Outcomes and safety of double-balloon enteroscopy in small bowel diseases: a single-center experience of 1531 procedures.

BACKGROUND: Double-balloon enteroscopy (DBE) has become a routine procedure in clinical practice for evaluation of small bowel diseases (SBDs). This study aimed to evaluate the diagnostic and therapeutic value of DBE in patients with suspected SBDs according to the patients' age and indications for the procedure. METHODS: The data of patients who underwent DBE at the endoscopy center of Changhai hospital between July 2013 and June 2018 were retrospectively reviewed. All features including demographic characteristics, indications, endoscopic findings, interventions and complications were collected. RESULTS: A total of 1291 consecutive patients who underwent 1531 DBE procedures (1375 diagnostic and 156 therapeutic) were included. The total diagnostic yield of DBE in cases of suspected SBDs was 58.9% (761/1291). The most common SBDs were Crohn's disease (CD) followed by tumors. The detection rates of CD and tumors by DBE were 18.3% (236/1291) and 12.7% (164/1291), respectively. The most frequent site of CD was the ileum (199/236, 84.3%), while that of tumors was the proximal small bowel (duodenum and jejunum, 115/164, 70.1%). In the young group (< 45 years), the majority of patients had CD, whereas tumors were the most common disease in the older group (≥ 45 years). The diagnostic yields for occult gastrointestinal bleeding (OGIB) and abdominal pain were 57.3% and 52.4%, respectively. In patients with OGIB, the detection rate of tumor was higher, whereas that of CD was higher in patients with abdominal pain. Polypectomy and foreign body removal were the predominant endoscopic interventions. DBE-associated complications were reported for 14 procedures (0.9%), including 3 diagnostic procedures (0.2%) and 11 therapeutic procedures (7.1%). CONCLUSION: DBE is a useful diagnostic tool for the investigation of SBDs, especially for CD and small bowel tumors. DBE is also a safe therapeutic procedure for polypectomy and foreign body removal.

Optimal Timing of First Abdominal Radiography after Gastrografin Administration for Small Bowel Obstruction.

BACKGROUND: Water-soluble contrast agent (WSCA) administration is commonly used to evaluate adhesive small bowel obstruction (SBO) either via a challenge or follow-through study. This analysis aimed to determine optimal timing to first abdominal radiograph after WSCA administration. MATERIALS AND METHODS: A post hoc review of the Eastern Association for the Surgery of Trauma SBO database was used to compare data from two institutions using different methodologies, either the small bowel follow through method or the challenge method, from March 2015-January 2018. The primary outcome was timing of contrast into the colon. Outcomes were also analyzed. A multivariate regression analysis controlled for age, sex, body mass index, previous SBO admissions, and abdominal surgeries. RESULTS: A total of 236 patients met inclusion and exclusion criteria (A, 119; B, 117). There were minor demographic differences between cohorts and no significant differences between institutions regarding the confirmed presence of WSCA in the colon, rates of operative intervention, length of operation, hospital length of stay, or 30-d readmission rates.Institution A, where the challenge method was practiced, had 95 (80%) patients with contrast to colon overall; four of 95 (4%) patients had confirmed contrast to colon at or before 7 h, and 89 of 95 (94%) patients had confirmed contrast to colon between 7.1 and 10 h. Institution B, where the small bowel follow through method was practiced, had 94 (80%) patients with contrast to colon overall; 73 of 94 (78%) patients had confirmed contrast to colon at or before 7 h, and 15 of 94 (16%) patients had confirmed contrast to colon between 7.1 and 10 h. CONCLUSIONS: Either method is effective for evaluation of SBO. Adding a radiograph at 4 h is feasible, could promote earlier disposition, be conducted as part of an emergency department protocol, and possibly allow for the selection of patients who are candidates for outpatient treatment.

Capsule endoscopy as a diagnostic test for Meckel's diverticulum.

OBJECTIVE: We described a case series of patients diagnosed with Meckel's diverticulum using capsule endoscopy (CE), reviewed the literature, and aimed to reveal the common CE characteristics of Meckel's diverticulum. MATERIALS AND METHODS: We reviewed a case series of Meckel's diverticulum in the Department of Gastroenterology, Beijing Shijitan Hospital Affliated to the Capital Medical University. In each case, primary upper endoscopy and colonoscopy failed to reveal a reason to explain the complaints (hematochezia in three cases and abdominal pain in one). CE (Pillcam SB2, Given Imaging, Yoqneam, Israel) was chosen as the next diagnostic test of choice and Meckel's diverticulum was detected by CE. Then, endoscopic characteristics and follow-up of Meckel's diverticulum were analyzed. RESULTS: 4 patients were enrolled. CE revealed Meckel's diverticulum in patients with different features. In case 1, CE revealed a typically double lumen sign and diaphragm sign, with visible blood. In case 2 and case 3, CE revealed a protruding lesion with/without erosion. In case 4, CE revealed multiple caved lesions, double lumen sign and capsule retention in an abnormal blind end for over 2 hours. CONCLUSION: Except double lumen sign, partial disappearance of normal mucosa and capsule retention, other CE findings could be used for the diagnosis of Meckel's diverticulum, such as protruding lesion, caved lesion, solitary polyp and stenosing lesion.

Clinical utility of double-balloon enteroscopy in children: A single-centre experience in South China.

AIM: Double-balloon enteroscopy (DBE) is a useful tool for the evaluation and treatment of small bowel disease. Limited clinical data are available regarding the indications, clinical findings and safety associated with the use of DBE in children. The aim of this study is to investigate the utility and safety of DBE in children. METHODS: A total of 72 DBE procedures were performed on 61 children at the Sixth Affiliated Hospital, Sun Yat-sen University, between 1 April 2013 and 31 December 2017. The clinical data were analysed retrospectively. RESULTS: DBE was attempted 72 times in 61 children (45 boys and 16 girls) of an age range between 6 and 14 years (mean age: 11.9 years). The most common indication for DBE was occult gastrointestinal bleeding and abdominal pain. The positive rate of abnormal findings was 77.5% (55/72). Most children showed non-specific enteritis and Crohn's disease. Eight children underwent successful therapeutic enteroscopy. No serious complication was observed in any child in this case series. CONCLUSION: DBE can be a useful diagnostic and therapeutic tool for small bowel disorders in children.

The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000-2015).

BACKGROUND: Seronegative villous atrophy (SNVA) is commonly attributed to coeliac disease (CD). However, there are other causes of SNVA. More recently angiotensin-2-receptor-blockers (A2RBs) have been reported as an association but data on SNVA have been limited to centres evaluating complex case referrals and not SNVA in general. OBJECTIVES: To provide clinical outcomes and associations in a large prospective study overseeing all newcomers with SNVA. DESIGN: Over a 15-year period (2000-2015) we evaluated 200 adult patients with SNVA at a UK centre. A diagnosis of either seronegative CD (SNCD) or seronegative non-CD (SN-non-CD) was reached. Baseline comparisons were made between the groups, with 343 seropositive CD subjects serving as controls. RESULTS: Of the 200 SNVA cases, SNCD represented 31% (n=62) and SN-non-CD 69% (n=138). The human leucocyte antigen (HLA)-DQ2 and/or DQ8 genotype was present in 61%, with a 51% positive predictive value for SNCD. The breakdown of identifiable causes in the SN-non-CD group comprised infections (27%, n=54), inflammatory/immune-mediated disorders (17.5%, n=35) and drugs (6.5%, n=13; two cases related to A2RBs). However, no cause was found in 18% (n=36) and of these 72% (n=26/36) spontaneously normalised duodenal histology while consuming a gluten-enriched diet. Following multivariable logistic regression analysis an independent factor associated with SN-non-CD was non-white ethnicity (OR 10.8, 95% CI 2.2 to 52.8); in fact, 66% of non-whites had GI infections. On immunohistochemistry all groups stained positive for CD8-T-cytotoxic intraepithelial lymphocytes. However, additional CD4-T helper intraepithelial lymphocytes were occasionally seen in SN-non-CD mimicking the changes associated with refractory CD. CONCLUSIONS: Most patients with SNVA do not have CD, in particular those who are not white. Furthermore, a subgroup with no obvious aetiology will show spontaneous histological resolution while consuming gluten. These findings suggest caution in empirically prescribing a gluten-free diet without investigation.

Clinical Practice Guideline for Enteroscopy.

Management of small bowel diseases has evolved since the advent of capsule endoscopy (CE) and balloon-assisted enteroscopy (BAE). One of the most common indications for enteroscopy is obscure gastrointestinal bleeding (OGIB), followed by small bowel stenosis, tumors, and inflammatory bowel disease. Although enteroscopes have been regarded as useful tools, correct guidelines are required to ensure that we manipulate these enteroscopes safely and efficiently in clinical practice. Herein, the Japanese Gastroenterological Endoscopy Society has developed 'Clinical Practice Guidelines for Enteroscopy' in collaboration with the Japanese Society of Gastroenterology, the Japanese Gastroenterological Association, and the Japanese Association for Capsule Endoscopy. These guidelines are based on the evidence available until now, but small bowel endoscopy is a relatively new technology, so the guidelines include recommendations based on a consensus reached among experts when the evidence has not been considered sufficient. These guidelines were not designed to be disease-based, but focus on how we should use small bowel CE and BAE in everyday clinical practice.

Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence.

OBJECTIVES: Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNF(deltaARE) mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement. DESIGN: Heterozygous TNF(deltaARE) mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis. RESULTS: GF-TNF(deltaARE) mice were free of inflammation in the gut and antibiotic treatment of CONV-TNF(deltaARE) mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNF(deltaARE) mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF(deltaARE) recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNF(deltaARE) mice with the human CD-related Escherichia coli LF82 did not induce ileitis. CONCLUSIONS: We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function.

Magnetic resonance enterography/enteroclysis in acquired small bowel diverticulitis and small bowel diverticulosis.

PURPOSE: Small bowel (SB) diverticulosis is a rare disorder that may entail serious complications, including SB diverticulitis. Both are often missed in imaging. Magnetic resonance enterography/enteroclysis (MRE) is increasingly used to assess SB disease; awareness of the appearance of SB diverticulitis is essential to ensure appropriate management. Our aim was to systematically describe imaging characteristics of SB diverticulosis and diverticulitis in MRE. METHODS: This retrospective, HIPAA-compliant study identified 186 patients with suspected SB diverticulosis/diverticulitis in medical databases of two tertiary medical centres between 2005 and 2011. Patients with surgically confirmed diagnoses of SB diverticulosis/diverticulitis were included. Two observers analyzed MR images for the presence, location, number, and size of diverticula, wall thickness, and mural and extramural patterns of inflammation. RESULTS: Seven patients were recruited. MRI analysis showed multiple diverticula in all (100 %). Diverticular size ranged from 0.5 to 6 cm. Prevalence of diverticula was higher in the proximal than the distal SB (jejunum 86 %, ileum 57 %, distal ileum43%). Diverticulitis occurred in 3/7 patients (43 %) showing asymmetric bowel wall thickening and focal mesenteric inflammation. CONCLUSION: SB diverticulitis demonstrates characteristic MRE imaging features to distinguish this rare disorder from more common diseases. Asymmetric, focal mesenteric and mural inflammation and presence of multiple diverticula are keys to diagnosis. KEY POINTS: • Small bowel diverticulosis and diverticulitis is rare and often missed in imaging • Acquired small bowel diverticula are variable in size and number • Small bowel diverticulitis demonstrates characteristic features on MR enterography/enteroclysis • A focal or segmental asymmetric small bowel inflammation should prompt the search for diverticula.

Clinical usefulness of transabdominal ultrasonography prior to patency capsule for suspected small-bowel strictures.

OBJECTIVE: Patency capsule (PC) examination has made it possible to perform capsule endoscopy (CE) in patients with a suspected small-bowel stricture. However, PC has some drawbacks, so we assessed the usefulness of transabdominal ultrasonography (TUS) prior to PC in patients with suspected small-bowel strictures to avoid unnecessary PC examination. PATIENTS AND METHODS: Fifty-two patients who underwent TUS prior to PC were enrolled in this study. TUS findings were classified as follows: intestinal narrowing and distension at the oral side (Type A); extensive bowel wall thickening (Type B); focal bowel wall thickening (Type C) or no abnormality detected (Type D). We evaluated the TUS and PC findings for the detection of small-bowel strictures. RESULTS: Double-balloon endoscopy (DBE) revealed small-bowel strictures in 13 of 50 patients (26%). TUS yielded Type B or C findings in 12 of 13 patients (92%), while PC revealed strictures in all 13 patients. In Crohn's disease (CD) patients with Type B TUS findings, 8 of 9 (89%) had small-bowel strictures on DBE. However, only two of six non-CD patients (33%) with Type B TUS findings had small-bowel strictures. The incidence of Type B strictures was significantly higher in CD patients. CONCLUSIONS: CD patients with Type B TUS findings should not undergo PC or CE because of the high rate of small-bowel strictures. Non-CD patients diagnosed with Type B TUS strictures, as well as patients diagnosed with Type C or D strictures should undergo CE after confirming small-bowel patency using PC.

Evaluation of radiation exposure dose at double-balloon endoscopy for the patients with small bowel disease.

UNLABELLED: Double-balloon endoscopy (DBE) is useful for the diagnosis and treatment of small bowel diseases. Although fluoroscopy is used to confirm the position of endoscope at DBE, the endoscopist does not have the knowledge with regard to the radiation exposure dose. In this study, we evaluated the absorbed dose during DBE in patients with suspected or established small bowel diseases. This was a retrospective study in which the estimated fluoroscopic radiation absorbed doses loaded on the small bowel and skin were determined according to the data of the referential X-ray experiment with a human body phantom. The subjects were 415 DBEs preformed in total. The mean small bowel absorbed doses on antegrade and retrograde DBEs were 42.2 and 53.8 mGy, respectively, showing that the organ dose applied in retrograde DBE was significantly higher (P<0.0001). The mean skin absorbed doses of them were 79.2 and 101.0 mGy, respectively, showing that the dose was also significantly higher on retrograde DBE (P<0.0001). Of 27 cases who were applied endoscopic balloon dilation, the mean fluoroscopy time was 16.0 minutes, and mean small bowel and skin absorbed doses were 121.9 and 228.9 mGy, respectively. In conclusion, endoscopist should be careful for reducing the organ exposure dose at DBE, particularly for the lower abdominal region. ABBREVIATIONS: Double-balloon enteroscopy (DBE), endoscopic balloon dilation (EBD), endoscopic mucosal resection (EMR), double-balloon endoscopic retrograde cholangiopancreatography (DBERCP), percutaneous coronary intervention (PCI).

Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology.

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

Anti-tumour necrosis factor agents reduce non-steroidal anti-inflammatory drug-induced small bowel injury in rheumatoid arthritis patients.

OBJECTIVE: The role of tumour necrosis factor α (TNFα) in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal damage remains unclear. We evaluated the preventive effect of anti-TNF therapy against NSAID-induced enteropathy in rheumatoid arthritis (RA) patients. DESIGN: Capsule endoscopy was performed in 95 consecutive RA patients who received NSAID for more than 3 months, with or without anti-TNF therapy over a period of 3 months. The findings were scored from 0 to 4: 0, normal; 1, red spots; 2, one to four erosions; 3, more than four erosions; and 4, large erosions/ulcers. The relationship between the use of anti-TNF therapy and the risk of severe damage (scores 3 or 4) or the most severe damage (score 4) was assessed using multiple logistic regression analysis. Furthermore, a propensity score matching analysis was performed to reduce the effects of TNF selection bias. RESULTS: By stratifying the patients on the basis of anti-TNF therapy, we obtained crude OR of 0.23 for severe damage (95% CI 0.09 to 0.65) and 0.37 for the most severe damage (95% CI 0.16 to 0.86). This protective effect of anti-TNF therapy remained robust to adjustments for baseline characteristics, with the adjusted OR for severe damage and the most severe damage ranging from 0.23 to 0.26 and 0.06 to 0.41, respectively. Propensity score matching yielded similar results and showed the protective effects of anti-TNF therapy against severe and most severe damage. CONCLUSIONS: Anti-TNF therapy may protect against NSAID-induced small intestinal damage in RA patients.

Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease.

OBJECTIVE: Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. DESIGN: Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. RESULTS: In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive Escherichia coli was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (-21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). CONCLUSIONS: The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier.

OBJECTIVE: Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. DESIGN: A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117(+) cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. RESULTS: Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. CONCLUSION: The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.