Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.

Low yield for routine laboratory checks in follow-up of coeliac disease.

AIM: To evaluate the yield of routine laboratory tests and Dual Energy X-ray Absorptiometry (DEXA) scans in coeliac disease. METHODS: A retrospective analysis of medical files of all followed-up patients with coeliac disease attending Rijnstate Hospital in 2016 was conducted with respect to blood tests of hemoglobin, vitamin B12, folate acid, iron status, calcium, vitamin D, glucose, thyroid function, DEXA-scans and related symptoms or signs of abnormalities. All patients had positive coeliac serology and/or biopsy-proven coeliac disease and attended regular visits after diagnosis. The chi-square test for trend was used for statistical analysis: a two-tailed probability of p < 0.05 was considered significant. RESULTS: We analyzed 250 patients with a median follow-up of 7.8 (1-22) years. At diagnosis, we found anemia in 24.4%, iron deficiency in 38%, folic acid deficiency in 22.6% and vitamin B12 deficiency in 15.9%. All deficiencies recovered within 1-2 years with or without supplements. Deficiencies or autoimmune diseases occurred in 50 patients (37 possibly coeliac-related) during follow-up. Twelve cases of coeliac-related deficiencies or autoimmune diseases occurred in patients with normal values at diagnosis of whom 10 were asymptomatic (incidence 10/1000 patient years). Osteoporosis and osteopenia were present in 23.3% and 35% at diagnosis. In most patients bone mineral density (BMD) improved or stabilized during follow up (p < 0.05), 8% deteriorated. CONCLUSIONS: The incidence of asymptomatic coeliac-related deficiencies or autoimmune diseases is low in patients with normal values at diagnosis. Therefore, routine laboratory screening is not necessary in this group: attending regular follow-up visits should be sufficient. DEXA scans are recommended.

High variation in treatment strategies for gastrointestinal angiodysplasias.

OBJECTIVE: Angiodysplasias (ADs) are the second leading cause of gastrointestinal bleeding in the elderly. The impact extends from no symptoms to chronic anaemia. Treatment guidelines are lacking. The aim of this study was to assess the current practice of gastrointestinal ADs and explore possible new research areas. On the basis of existing evidence, we would like to propose a treatment algorithm. METHODS: We administered a 19-item web-based survey to gastroenterologists in the Netherlands between February and April of 2015. RESULTS: A total of 111 (response rate 28%) gastroenterologists completed the survey (mean age=47 years; 24% women). The respondents identified Von Willebrand disease (17%), chronic kidney disease (21%) and aortic stenosis (77%) as risk factors for the development of ADs. Colonoscopy (54%) and esophagogastroduodenoscopy (43%) were the preferred first tools to screen for ADs. The favoured (77%) first treatment option is endoscopic argon plasma coagulation, whereas 20% start iron supplementation or blood transfusions. Treatment strategy is mostly (65%) based on the location of the ADs. Small bowel ADs are considered the most difficult to treat, because of the need for balloon enteroscopy. Of the gastroenterologists, 13% would treat ADs as a coincident finding during endoscopy. Medical therapy is mostly started in refractory ADs, and thalidomide (40%) is preferred over octreotide (19%). Thalidomide is more preferred by gastroenterologists working in a teaching hospital. CONCLUSION: Identification of risk factors and treatment of ADs vary widely between gastroenterologists in the Netherlands. Further research is needed to create an evidence-based guideline and thereby optimize the management of symptomatic ADs.

High mucosal healing rates in 5-ASA-treated ulcerative colitis patients: results of a meta-analysis of clinical trials.

BACKGROUND: Recently, mucosal healing (MH) is regarded as an important treatment goal in ulcerative colitis (UC). 5-Aminosalicylates (5-ASA) are the standard treatment in mild-to-moderate UC, but the effect on MH is less known. The aim of this study was to systematically review the medical literature in order to compare different preparations of 5-ASA for the effect on MH. METHODS: We conducted a structured search of PubMed and the Cochrane Central Register of Controlled Trials to identify randomized controlled clinical trials with 5-ASA in UC providing data about MH. We calculated the sample size-weighted pooled proportion of patients with MH, and performed meta-analysis of head-to-head comparisons. RESULTS: Out of 645 hits, we included 90 treatment arms, involving 3977 patients using oral 5-ASA (granulate and tablets) and 2513 patients using rectal 5-ASA (suppositories, enema, and foam). Overall, 43,7% of 5-ASA treated patients achieved MH (oral 36,9%; rectal 50,3%). In oral studies, 49% of patients using granulate (7 treatment-arms) achieved MH compared to 34,9% using tablets (43 treatment-arms). In rectal studies the proportion of MH was 62% for suppositories (eight treatment arms), 51% for foam (nine treatment arms), and 46% for enema (23 treatment arms), respectively. CONCLUSIONS: 5-ASA preparations achieved MH in nearly 50% of UC patients. There were no significant differences in MH between the various 5-ASA agents, either in the oral or the rectal treatment groups.

Training innovations in gastroenterology and educational resources: a new vision of gastrointestinal education across Europe.

To define a new educational strategy for the United European Gastroenterology Federation (UEGF) to be followed and implemented in the near future. UEGF organized a consensus-based strategy meeting with stakeholders and key decision makers in European Gastroenterology on Training Innovations in Gastroenterology and Educational Resources. In May 2010, in an 'open-face conference' at Starnberg, Germany, 59 specialists in gastroenterology, hepatology, and related fields from 15 countries and 16 societies participated. Breakout sessions identified the key problem areas, possible solutions, and formulated statements subsequently voted upon in plenum. A majority of the formulated statements (59%) reached a strong agreement. Topics in which UEGF should focus are the future educational activities that include developing ways to advocate multidisciplinarity and integration between levels of care and specialties, ways to improve quality of care, and the development of training tools. The successful outcome of the Training Innovations in Gastroenterology and Educational Resources conference was achieved with the production of a strategy layout for new UEGF educational activities. There was an agreement that improvement in topics related to multidisciplinarity and professionalism, which is crucial for further development. An open-face conference, such as that embodied by the Training Innovations in Gastroenterology and Educational Resources meeting, was shown to be an effective tool in identifying the key problem areas in education and in formulating new strategies.

2-(18F)-fluoro-2-deoxy-D-glucose positron emission tomography detects clinical relevant adenomas of the colon: a prospective study.

PURPOSE: 2-(18F)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is a noninvasive imaging technique used clinically to detect malignant tumors. FDG-PET has been established as a tool for diagnosis of recurrent or metastatic colorectal carcinoma. Several case series suggest that FDG-PET also detects larger adenomas. The goal of this study was to investigate whether FDG-PET is able to detect colonic adenomas. PATIENTS AND METHODS: FDG-PET was performed in 100 consecutive patients in whom colonic adenomas were suspected on barium enema (n = 47) or sigmoidoscopy (n = 53). A positive scan was defined as focal large bowel FDG accumulation. FDG-PET was followed in all cases by colonoscopy, and removed adenomas were examined histopathologically. RESULTS: Colonoscopy confirmed the presence of adenomas in 68 of 100 patients. In 35 patients, there was focal FDG accumulation at site of the adenoma. The sensitivity of FDG-PET increased with adenoma size (21%, adenomas 1 to 5 mm; 47%, 6 to 10 mm; and 72%, > 11 mm). The sensitivity of FDG-PET also increased with the grade of dysplasia (33%, low grade; 76%, high grade; and 89%, carcinomas). The overall specificity was 84%. CONCLUSION: FDG-PET detects colonic adenomas and the diagnostic test characteristics improve with size and grade of dysplasia of the adenoma.

Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release.

The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process. In the present study we demonstrate that although NOD2 is required for recognition of peptidoglycan, this leads to strong synergistic effects on TLR2-mediated production of both pro- and anti-inflammatory cytokines. Defective IL-10 production in patients with Crohn's disease bearing loss of function mutations of NOD2 may lead to overwhelming inflammation due to a subsequent Th1 bias. In addition to the potentiation of TLR2 effects, NOD2 is a modulator of signals transmitted through TLR4 and TLR3, but not through TLR5, TLR9, or TLR7. Thus, interaction between NOD2 and specific TLR pathways may represent an important modulatory mechanism of innate immune responses.