A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B.

BACKGROUND & AIMS: Nucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach. METHODS: In this multicenter, randomized-controlled trial, 166 HBeAg-negative patients with chronic hepatitis B on continuous long-term NUC treatment, with HBV DNA <172 IU/ml (1,000 copies/ml) for ≥4 years, were randomized to either stop (Arm A) or continue NUC treatment (Arm B) for a 96-week observation period. In total, 158 patients were available for final analysis, 79 per arm. The primary endpoint was sustained HBsAg loss up to week 96. RESULTS: Our study met its primary objective by demonstrating HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in Arm A and in no patient in Arm B (p = 0.006). Among patients with baseline HBsAg levels <1,000 IU/ml, seven (28%) achieved HBsAg loss. In Arm A, re-therapy was initiated in 11 (13.9%) patients, whereas 32 (40.5%) patients achieved sustained remission. A decrease of HBsAg >1 log IU/ml was observed in 16 patients (20.3%) in Arm A and in one patient (1.3%) in Arm B. No serious adverse events related to treatment cessation occurred. CONCLUSIONS: Cessation of NUC treatment was associated with a significantly higher rate of HBsAg loss than continued NUC treatment, which was largely restricted to patients with end of treatment HBsAg levels <1,000 IU/ml. IMPACT AND IMPLICATIONS: As HBeAg-negative patients with chronic hepatitis B on nucleos(t)ide analogues (NUCs) rarely achieve functional cure, treatment is almost always lifelong. The STOP-NUC trial was conducted to investigate whether discontinuing long-term NUC treatment can increase the cure rate. We found that some patients achieved functional cure after stopping NUCs, which was especially pronounced in patients with HBsAg levels <1,000 at the end of NUC treatment, and that many did not need to resume therapy. The results of the Stop-NUC trial provide evidence for the concept of stopping NUC treatment as a therapeutic option that can induce functional cure.

Gene variants of the SLC2A5 gene encoding GLUT5, the major fructose transporter, do not contribute to clinical presentation of acquired fructose malabsorption.

BACKGROUND: While role of ALDOB-related gene variants for hereditary fructose intolerance is well established, contribution of gene variants for acquired fructose malabsorption (e.g. SLC2A5, GLUT5) is not well understood. METHODS: Patients referred to fructose breath test were further selected to identify those having acquired fructose malabsorption. Molecular analysis of genomic DNA included (I) exclusion of 3 main ALDOB gene variants causing hereditary fructose intolerance and (II) sequencing analysis of SLC2A5 gene comprising complete coding region, at least 20 bp of adjacent intronic regions and 700 bp of proximal promoter. RESULTS: Among 494 patients, 35 individuals with acquired fructose malabsorption were identified based on pathological fructose-breath test and normal lactose-breath test. Thirty four of them (97%) had negative tissue anti-transglutaminase and/or deamidated gliadin antibodies in their medical records. Molecular analysis of SLC2A5 gene of all 35 subjects identified 5 frequent and 5 singular gene variants mostly in noncoding regions (promoter and intron). Allele frequencies of gene variants were similar to those reported in public databases strongly implying that none of them was associated with acquired fructose malabsorption. CONCLUSIONS: Gene variants of coding exons, adjacent intronic regions and proximal promoter region of SLC2A5 gene are unlikely to contribute to genetic predisposition of acquired fructose malabsorption.

Anti-TNFα treatment in Crohn's disease: Impact on hepatic steatosis, gut-derived hormones and metabolic status.

BACKGROUND AND AIMS: An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis. METHODS: This cross-sectional study evaluated patients with established CD, with and without anti-TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. RESULTS: Patients on anti-TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. CONCLUSIONS: Anti-TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.

[Treatment of eosinophilic esophagitis - advancements and perspectives]. / Therapie der eosinophilen Ösophagitis ­ Fortschritte und Perspektiven.

In recent years significant progress has been made in the treatment of eosinophilic esophagitis (EoE), especially in the area of topical corticosteroids. Novel EoE-specific formulations have been developed and first approvals have been obtained for induction and maintenance of remission in adult EoE patients with the orodispersible budesonide tablet in Germany and other European and non-EU countries. A novel budesonide oral suspension is currently under priority review by the FDA for first approval in the U.S. In contrast, the scientific evidence on the efficacy of proton pump inhibitors remains limited. Moreover, new biologicals have been identified which showed promising results in phase 2 trials and are now being studied in phase 3. This article aims to summarize and discuss recent advances and perspectives in the treatment of EoE.

[Bile acid diarrhea, stepchild of chronic diarrhea - prevalence, diagnosis and treatment. Update 2021]. / Chologene Diarrhö, Stiefkind der chronischen Diarrhö ­ Prävalenz, Diagnostik und Therapie. Update 2021.

Bile acid diarrhea is one of the most frequently undiagnosed causes of chronic diarrhea. A variety of different pathophysiologic causes can underlie chronic diarrhea. Even after exclusion of the more frequent causes, up to 5 % of the population remains affected by unexplained chronic diarrhea. In up to 50 % within this cohort, bile acid diarrhea is the underlying cause.The various pathophysiologies leading to bile acid diarrhea are well characterized. In this way, bile acid diarrhea can be divided into primary, secondary and tertiary subtypes. Common to all causes is the increased amount of bile acids in the colon and in the faeces and the resulting secretory-osmotic diarrhea, in more severe forms in combination with steatorrhea. The diagnosis of bile acid diarrhea follows a clear algorithm which, in addition to the search for the cause and possibly a therapeutic trial, recognizes the 75SeHCAT test as the reference method for the detection of an increased loss of bile acids. In view of the chronic nature of the symptoms and the need for permanent, lifelong therapy, the use of a one-time, reliable diagnostic test is justified, though the test is currently only available at a few centers. In addition to the treatment of identifiable underlying diseases, the current treatment includes the use of drugs that bind bile acids, with additional nutritional recommendations and vitamin substitutions.The present review article summarizes the pathophysiology and importance of bile acid diarrhea and discusses the current approach towards diagnosis and treatment.

Budesonide Orodispersible Tablets Maintain Remission in a Randomized, Placebo-Controlled Trial of Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder. Swallowed topical-acting corticosteroids are effective in bringing active EoE into remission. However, it is not clear whether these drugs are effective for long-term maintenance of remission. METHODS: We performed a double-blind trial to compare the efficacy and safety of 2 dosages of a budesonide orodispersible tablet (BOT) vs placebo in maintaining remission of EoE. Maintenance of remission was defined as absence of clinical and histologic relapse and no premature withdrawal for any reason. Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given BOT 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks. RESULTS: At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo). Median time to relapse in the placebo group was 87 days. The frequency of adverse events was similar in the BOT and placebo groups. Morning serum levels of cortisol were in the normal range at baseline and did not significantly change during treatment. Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment. CONCLUSIONS: In a phase 3 trial, up to 48 weeks of treatment with BOT (0.5 mg or 1.0 mg twice daily) was superior to placebo in maintaining remission of EoE. Both dosages were equally effective and well tolerated. EudraCT number; 2014-001485-99; ClinicalTrials.gov number, NCT02434029.

[Eosinophilic Esophagitis Update: New Guidelines of the European Study Group EUREOS]. / Eosinophile Ösophagitis Update 2017: Neue Leitlinien der europäischen Studiengruppe EUREOS.

Eosinophilic esophagitis is now considered to be a frequent chronic esophageal disease and is one of the most common causes for dysphagia and bolus obstruction in children and adults. The increasing significance and new scientific insights in this disorder required an update of currently existing guidelines. Therefore, the European Study Group of Eosinophilic Esophagitis (EUREOS) has elaborated new guidelines for the management of eosinophilic esophagitis, based on a systematic literature search and, for the first time, using the GRADE methodology (Grading of Recommendations Assessment, Development, and Evaluation). The aim of the present article is to summarize and comment on new developments and clinical recommendations of this guideline to further increase the awareness for this relevant esophageal disease.

Clinical management of eosinophilic esophagitis - a nationwide survey among gastroenterologists in Germany.

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly recognized immune-mediated esophageal disease and a common cause for dysphagia and food bolus obstruction. The aim of this study was to evaluate the current clinical management of EoE among adult gastroenterologists in Germany. METHODS: We performed a cross-sectional study of 1393 adult gastroenterologists using a questionnaire containing 22 questions to general, diagnostic, and therapeutic aspects of EoE. The self-administered online survey was conducted between November 2017 and February 2018. Data capture and analysis was performed using SurveyMonkey. RESULTS: The overall responder rate was 29.6 %. More than half of the responders (54.9 %) felt to observe a significant increase of EoE patients. The EREFS score was mostly either unknown (44.3 %) or not routinely used (52.2 %). If EoE was suspected, most responders obtained multiple esophageal biopsies (n = 3 - 4: 35.7 %; n > 4: 61.6 %). The preferred primary treatment was proton pump inhibitors (PPI) in 37.2 % and topical steroids in 35.0 % of responders. PPI regimens were highly diverse, with only half of responders using high-dose PPI regimens. Allergy testing was often initiated (always 25.4 %, sometimes 48.9 %). The most common dietary therapy was 6-food elimination diet (52 %), followed by allergy test-directed diets (16 %) and 2-food elimination diet (16.5 %). The majority of responders indicated a need for long-term treatment (i. e., 23 % of responders in > 50 % their patients and 47.7 % of responders in 25 - 50 % of their patients). CONCLUSIONS: Among gastroenterologists in Germany, substantial variation in the adherence to published EoE guidelines appears to exist. This indicates the need for intensified education and national guidelines in order to optimize and harmonize the clinical management of EoE patients.

Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial.

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.

Helicobacter pylori eradication therapy is not associated with the onset of inflammatory bowel diseases. A case-control study.

BACKGROUND AND AIMS: A negative association between H. pylori and inflammatory bowel disease (IBD) has been previously reported. There were also case reports suggesting a new onset of IBD 6-12 months after H. pylori eradication therapy. In a case-control study we investigated whether previous H. pylori eradication therapy was associated with the risk of developing IBD. METHODS: IBD outpatients with both Crohn´s disease (CD) and ulcerative colitis (UC) were enrolled. Age- and sex-matched blood donors served as controls in a 1:2 fashion. Information on demographics, medical history, previous H. pylori infection and eradication therapy was recorded. Serum samples for H. pylori serology testing (anti-H. pylori-IgG and anti-CagA-IgG) were obtained. Controls that received H. pylori eradication therapy during the 12 months previous to enrollment were excluded. RESULTS: Overall, 127 IBD patients (CD N= 90; UC N=37) and 254 controls were enrolled. The prevalence of H. pylori infection (positive H. pylori serology and/or previous eradication) in IBD patients and controls was 11% and 23%, respectively (OR 0.4, 95% CI 0.21-0.74, p<0.003). Four patients (3%) developed IBD (3 MC and 1 CU) after receiving successful H. pylori eradication (latency 6-12 months). The rate of previous H. pylori eradication therapy in patents who successively developed IBD was lower but not statistically different from that observed in the control group (OR 0.43, 95% CI 0.14-1.29, p=0.16). CONCLUSIONS: In our study previous H. pylori eradication therapy was not associated with the onset of IBD. Whether in a subgroup of patients, H. pylori eradication therapy may trigger a latent IBD, cannot be excluded.

Circulating and Fecal microRNAs as Biomarkers for Inflammatory Bowel Diseases.

Background: Assessment of the disease activity in inflammatory bowel disease (IBD) is essential for adequate treatment management and reliable noninvasive biomarkers for verification of mucosal healing are still needed. MicroRNAs (miRNAs) are differentially expressed in IBD and cancer. We aimed to evaluate the potential of circulating and fecal miRNAs as diagnostic biomarkers for IBD. Methods: In this proof-of-principle study we used 2 independent patient cohorts. Testing cohort (n = 96) included serum and fecal samples from controls (n = 35) and IBD patients (n = 61) including 43 patients with Crohn's disease (CD), 18 with ulcerative colitis (UC) with an active disease (n = 38), or in remission (n = 23). Validation cohort included fecal samples from patients with calprotectin/endoscopy-confirmed active disease (n = 30) or in remission (n = 15). Target-based approach (miR-16, miR-21, miR-155, and miR-223) has been used to evaluate miRNA expression. Results: Sera samples from IBD patients showed higher level of miR-16, miR-21, and miR-223, but not miR-155, compared to controls and was higher in CD than in UC patients. Much stronger miRNA expression changes were observed in feces from IBD patients for all studied miRNAs with highest expression of miR-155 and miR-223 in testing and validation cohorts. MiRNA expression correlated with clinical remission, however, only fecal but not circulating miRNAs, correlated with surrogate parameters such as fecal calprotectin or C-reactive protein. Conclusions: Our data provide a novel evidence for differential expression level of fecal miRNAs in IBD. We demonstrate that miRNAs in feces correlate with disease activity and may be considered as potential tool for the further biomarker research in IBD. 10.1093/ibd/izy046_video1izy046.video15794822319001.

Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.

INTRODUCTION: Eosinophilic esophagitis (EoE) is one of the most prevalent esophageal diseases and the leading cause of dysphagia and food impaction in children and young adults. This underlines the importance of optimizing diagnosys and treatment of the condition, especially after the increasing amount of knowledge on EoE recently published. Therefore, the UEG, EAACI ESPGHAN, and EUREOS deemed it necessary to update the current guidelines regarding conceptual and epidemiological aspects, diagnosis, and treatment of EoE. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted up to August 2015 and periodically updated. The working group consisted of gastroenterologists, allergists, pediatricians, otolaryngologists, pathologists, and epidemiologists. Systematic evidence-based reviews were performed based upon relevant clinical questions with respect to patient-important outcomes. RESULTS: The guidelines include updated concept of EoE, evaluated information on disease epidemiology, risk factors, associated conditions, and natural history of EoE in children and adults. Diagnostic conditions and criteria, the yield of diagnostic and disease monitoring procedures, and evidence-based statements and recommendation on the utility of the several treatment options for patients EoE are provided. Recommendations on how to choose and implement treatment and long-term management are provided based on expert opinion and best clinical practice. CONCLUSION: Evidence-based recommendations for EoE diagnosis, treatment modalities, and patients' follow up are proposed in the guideline.

Correlation of High-Resolution Manometric Findings with Symptoms of Dysphagia and Endoscopic Features in Adults with Eosinophilic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) presents with dysphagia, but data about motility patterns using high-resolution manometry (HRM) are rare. We aimed at evaluating esophageal motility patterns in EoE and their correlation to endoscopic and dysphagia scores. METHODS: Twenty-six EoE patients and 23 controls were included after 4 weeks of treatment with proton pump inhibitors. Dysphagia and endoscopic scores were evaluated before performing HRM. EoE patients were classified to have fibrostenotic (FS) or inflammatory (IF) type. HRM analysis was performed according to the Chicago classification (CC) system. RESULTS: According to the CC, the HRM findings in EoE and controls were normal in 11 (42%) and 20 (88.5%), p < 0.0001. Weak and failed peristaltic integrity was only seen in EoE patients (failed 1/2.7%, weak 7/26.9%, p = 0.004). Of the EoE patients, 17 had IF and 9 presented with FS type. HRM parameters showed no differences according to the EoE subtype. The endoscopic score in the FS subtype was significantly higher than in EoE with IF subtype (5.33 vs. 3.58, p = 0.001). No significant difference was seen in dysphagia scores in EoE subtypes. DISCUSSION: HRM findings in EoE are often diagnostic, but they are non-specific and do not correlate with the severity of dysphagia or endoscopic appearance. The clinical impact of HRM in EoE needs further evaluation.

[Eosinophilic Esophagitis - Update - Pathogenesis, Diagnosis and Therapy]. / Eosinophile Ösophagitis ­ Neues zur Pathogenese, Diagnostik und Therapie.

Eosinophilic esophagitis (EoE) is a clinicopathological condition of the esophagus that has become increasingly recognised over the last decade. EoE represents a chronic immune-mediated inflammatory disease of the esophagus. In adults dysphagia is the predominant symptom. Upper gastrointestinal endoscopy is required in order to take biopsies from the esophagus. The diagnose is confirmed histologically by typical eosinophilic infiltration of the esophagus mucosa. Until now there is no approved therapy world-wide although we know that topic and systemic steroids are highly effective in EoE. Elimination diet is another option and in well selected patients endoscopic balloon dilation represents a therapeutic possibility.

Fecal calprotectin: a marker for clinical differentiation of microscopic colitis and irritable bowel syndrome.

BACKGROUND: The aim of this study is to compare two methods for measuring fecal calprotectin (FC) concentration and to evaluate the possibility of differentiation between microscopic colitis (MC) and irritable bowel syndrome (IBS). METHODS: Twenty-three patients with MC (six patients with active disease and 17 patients retested in remission) and 20 patients with IBS were prospectively included in this study. Active disease state of MC was determined by clinical symptoms of >3 bowel movements per day and histological correlate. All patients underwent ileocolonoscopy, including segmental biopsy samples for histology. FC levels in stool samples were analyzed using a rapid test system (Quantum Blue(®)) and an enzyme-linked immunosorbent assay (ELISA). RESULTS: FC levels were significantly higher in patients with active MC (median 48 µg/g [23-106]) compared to patients with IBS (median 2 µg/g [1-111.83]), P=0.0001 using an ELISA. FC level of patients with MC in remission was 22 µg/g (1-106.4), which is similar to those identified in patients with IBS. The difference of FC levels between active MC and IBS was not detected by the FC rapid test (P=0.635). DISCUSSION: FC levels might serve as parameter for differentiation between patients with active MC and IBS. Since there is no surrogate marker available at present for MC, FC appears to be a candidate for differentiating MC from IBS. CONCLUSION: High FC levels, which were analyzed by ELISA, are a potential marker for patients with active MC compared to those with IBS. The FC rapid test was less suitable for this purpose.

A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.

OBJECTIVE: To investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE). DESIGN: Adults with active EoE (n=76) randomly received 14 days' treatment with either BET 2×1 mg/day (BET1, n=19) or BET 2×2 mg/day (BET2, n=19), or BVS 2×5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm(2 )hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patient's preference for drug formulation. RESULTS: Histological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients. CONCLUSIONS: BET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation. CLINICALTRIALSGOV NUMBER: NCT02280616; EudraCT number, 2009-016692-29.