Induction and maintenance of mucosal healing in Crohn's disease with ustekinumab in clinical practice across all care levels in Germany (MUCUS).

The impact of ustekinumab (UST) on mucosal- and fistula healing and extraintestinal manifestations (EIM) in Crohn's disease (CD) were not fully elucidated in the registration trials. In this prospective, multicenter study (EudraCT number: 2017-005151-83) we evaluated the German label real-world-effectiveness of UST to achieve the primary endpoint of combined clinical and endoscopic response at week 52 and several secondary endpoints. Of 79 screened we enrolled 52 patients (female n = 28, bionaïve n = 13, biologic n = 39). At week 52 (per protocol analysis), 52% (n = 13/25) of patients achieved the primary endpoint [50% (n = 3/6) in the bionaïve, 45.5% (n = 5/11) biologic, 62.5% (n = 5/8 ) multiple biologics cohorts, respectively with age as independent predictor [OR 95% CI 0.933 (0.873, 0.998) p = 0.043], 60% (n = 15/25) achieved endoscopic response [50% (n = 3/6) in the bionaïve, 54.5% (n = 6/11) biologic, 75% (n = 6/8) multiple biologics cohorts, respectively], 36% (n = 9/25) achieved endoscopic remission [50% (n = 3/6) in the bionaïve, 27.3% (n = 3/11) biologic, 37.5% (n = 3/8) multiple biologics cohorts, respectively], 48% (n = 12/25) achieved mucosal healing [50% (n = 3/6) in the bionaïve, 36.4% (n = 4/11) biologic, 62.5% (n = 5/8) multiple biologics cohorts, respectively]. All achieved a fistula response and 33.3% (n = 1/3) in the multiple biologics group fistula remission at week 52. EIM decreased (week 0 28.2% vs. week 52 8%). CRP, FCP, PRO-2, EQ-5D-5L improved throughout. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event, in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to UST discontinuation, but no very severe events or deaths. The effectiveness of UST was better than in the registration trials.

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.

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.

[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.

Evidence of Crohn's disease-related anti-glycoprotein 2 antibodies in patients with celiac disease.

BACKGROUND: Autoantibodies to exocrine-pancreatic glycoprotein 2 (anti-GP2) are Crohn's disease (CD) markers. However, CD-specific antibodies have also been found in celiac-disease (CeD) patients, in which type 1 diabetes-specific autoantibodies against endocrine pancreatic targets can be present. We investigated whether anti-GP2 are also present in CeD, a disease like CD which is also characterised by intestinal mucosal inflammation with barrier impairment. METHODS: Antibodies against GP2, tissue transglutaminase (tTG), deamidated gliadin (dGD), glutamic decarboxylase (GAD), and islet antigen-2 (IA2) were tested in sera from 73 CD patients, 90 blood donors (BD), and 79 (58 de novo) CeD patients (2 consecutive sera were available from 40 patients). RESULTS: IgA and/or IgG anti-GP2 were found in 15/79 (19.0%) CeD patients on at least one occasion, in 25/73 (34.2%) CD patients, and in 4/90 (4.4%) BD (CeD vs. CD, p=0.042; BD vs. CeD and CD, p<0.001, respectively). Amongst the 58 de novo CeD patients, anti-GP2 IgA and/or IgG were present in 11 (19.0%). Anti-GP2 IgA was significantly less prevalent in CeD compared with CD (p=0.004). Anti-GP2 IgA and IgG in CD patients demonstrated a significantly higher median level compared to patients with CeD (p<0.001, p=0.008, respectively). IgA anti-GP2 levels correlated significantly with IgA anti-tTG and anti-dGD levels in CeD Spearman's coefficient of rank correlation (ρ)=0.42, confidence interval (CI): 0.26-0.56, p<0.001; ρ=0.54, CI 0.39-0.65, p<0.001, respectively. CONCLUSIONS: The presence of anti-GP2 in CeD patients supports the notion that loss of tolerance to GP2 can probably be a manifestation of an autoinflammatory process in this intestinal disorder.

Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn's disease.

BACKGROUND: Glycoprotein 2 (GP2) was discovered as the major autoantigen of Crohn's disease (CD)-specific pancreatic autoantibodies (PAB). We investigated anti-GP2 IgA and IgG antibodies as novel serological parameters in CD and assessed their association with distinct disease phenotypes. METHODS: Anti-GP2 and anti-Saccharomyces cerevisiae (ASCA) IgA and IgG were detected by ELISA employing recombinant human GP2 and phosphopeptidomannan, respectively and PAB by indirect immunofluorescence (IIF) in 271 sera, 169 with CD and 102 with ulcerative colitis (UC). As healthy controls 160 adult blood donors and 65 children were included. RESULTS: Anti-GP2 IgG and/or IgA were more prevalent in CD (51/169, 30.2%) than in UC (9/102, 8.9%) patients and in controls (9/225, 4%) (p < 0.001 respectively). ASCA IgG and/or IgA were present in 60/169 (35.5%) in CD and in 7/102 (6.9%) in UC patients (p < 0.001). CD patients with ileocolonic location (L3) showed a significantly higher prevalence of anti-GP2 and ASCA IgA and/or IgG (40/113 and 48/113, respectively; p < 0.05 for both comparisons), whereas CD patients with colonic location (L2) revealed a significantly diminished prevalence for these autoantibody specificities (2/32 and 5/32, respectively, p < 0.05 for both). Anti-GP2 IgG were significantly more prevalent in CD patients with stricturing behaviour (B2) and perianal disease (7/11, p < 0.02) and less prevalent in those with penetrating behaviour (B3) and perianal disease (4/31, p < 0.05). The occurrence of anti-GP2 IgA and/or IgG was significantly more prevalent in CD patients with age at diagnosis of ≤16 years (16/31, p < 0.009). Prevalence of one or more anti-GP2 or ASCA IgA and/or IgG was significantly higher in L3, B2, and A1 and lower in L2 (68/113, 27/41, 23/31, 6/32; p < 0.04, respectively). CONCLUSIONS: Anti-GP2 IgG and IgA, constituting novel CD specific autoantibodies, appear to be associated with distinct disease phenotypes identifying patients at a younger age, with ileocolonic location, and stricturing behaviour with perianal disease.

Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, are new markers in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease (IBD) characterized by reactivity against microbial and self antigens. Zymogen granule glycoprotein 2 (GP2) was identified as the major autoantigen of CD-specific pancreatic autoantibodies (PAB). METHODS: Human GP2 was expressed in the Spodoptera frugiperda 9 (Sf9) cell line using the baculovirus system, purified by Ni-chelate chromatography, and used as antigen for anti-GP2 IgA and IgG assessment by enzyme-linked immunosorbent assays (ELISA). Antibodies to mannan of Saccharomyces cerevisiae (ASCA), PAB, and anti-GP2 were investigated in sera of 178 CD patients, 100 ulcerative colitis (UC) patients, and 162 blood donors (BD). RESULTS: Anti-GP2 IgG and IgA were found in 48/72 (66.7%) and 23/72 (31.9%) PAB positive and 5/106 (4.7%) and 1/106 (0.9%) PAB negative CD patients (p<0.0001), respectively. CD patients displayed significantly higher reactivity to GP2 than UC patients and BD (p<0.0001), respectively. Occurrence of anti-GP2 antibodies correlated with PAB reactivity (Spearmen's rho=0.493, p<0.00001). There was a significant relationship between the occurrence of ASCA IgG and anti-GP2 IgG (p=0.0307). CONCLUSIONS: Anti-GP2 IgG and IgA constitute novel CD specific autoantibodies, the quantification of which could improve the serological diagnosis of IBD.

Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in vivo.

Pituitary adenylate cyclase-activating peptide (PACAP) is an important neuropeptide and immunomodulator in various tissues. Although this peptide and its receptors (ie, VPAC1R, VPAC2R, and PAC1R) are expressed in human skin, their biological roles are unknown. Therefore, we tested whether PACAP regulates vascular responses in human skin in vivo. When injected intravenously, PACAP induced a significant, concentration-dependent vascular response (ie, flush, erythema, edema) and mediated a significant and concentration-dependent increase in intrarectal body temperature that peaked at 2.7°C. Topical application of PACAP induced marked concentration-dependent edema. Immunohistochemistry revealed a close association of PACAP-immunoreactive nerve fibers with mast cells and dermal blood vessels. VPAC1R was expressed by dermal endothelial cells, CD4+ and CD8+ T cells, mast cells, and keratinocytes, whereas VPAC2R was expressed only in keratinocytes. VPAC1R protein and mRNA were also detected in human dermal microvascular endothelial cells. The PACAP-induced change in cAMP production in these cells demonstrated VPAC1R to be functional. PACAP treatment of organ-cultured human skin strongly increased the number of CD31+ vessel cross-sections. Taken together, these results suggest that PACAP directly induces vascular responses that may be associated with neurogenic inflammation, indicating for the first time that PACAP may be a crucial vascular regulator in human skin in vivo. Antagonists to PACAP function may be beneficial for the treatment of inflammatory skin diseases with a neurogenic component.

Whipple's disease: an endoscopic and histologic study.

BACKGROUND/AIM: Primary gastrointestinal tract involvement occurs in one third of patients with Whipple's disease (WD). Nevertheless, there are scant data on the endoscopic appearance of WD. The aim of this study was to provide a detailed endoscopic-pathologic assessment of patients with WD. METHODS: Four patients with a diagnosis of WD who underwent endoscopic evaluation by a single endoscopist were included. Published information on WD was reviewed in detail, focusing on the endoscopic and histologic features of this disease. RESULTS: WD had a wide range of endoscopic features, including edema, brown discoloration of the mucosa, erythematous spots, subepithelial hemorrhages, and megaduodenum. Magnification endoscopy revealed engorged and flattened villi, villi filled with white material, and white ring-like structures inside of the villi and multiple yellow spots. The histological features of WD include a coarse granular cytoplasm and foamy macrophages that stain strongly with the period acid-Schiff reagent. CONCLUSIONS: Gastrointestinal WD has a wide spectrum of endoscopic appearance. Magnification endoscopy enhances the mucosal details. Esophagogastroduodenoscopy with procurement of biopsy specimens from the duodenum was an accurate method for the diagnosis of WD in this case series.

Breath and string test: a diagnostic package for the identification of treatment failure and antibiotic resistance of Helicobacter pylori without the necessity of upper gastrointestinal endoscopy.

AIM: Helicobacter pylori (H pylori) resistance after failed eradication has a major impact on the outcome of a further treatment regimen. The aim of this study was to assess the validity of a non-invasive strategy using the 13C-urea breath test (UBT) and the gastric string test in identifying post-treatment resistance of H pylori. METHODS: The UBT was routinely performed 4 to 6 wk after H pylori eradication therapy. Forty-two patients (24 females, 18 males, mean age 48 years) with a positive UBT were included in the study. A gastric string test using a capsule containing a 90 cm-long nylon fiber was performed. Before the capsule was swallowed, the free end of the string was taped to the cheek. After one hour in the stomach, the string was withdrawn. The distal 20 cm of the string was inoculated onto an agar plate and processed under micro-aerophilic conditions. Following the string test, upper gastrointestinal endoscopy was performed to obtain gastric biopsies for conventional culture. RESULTS: H pylori was successfully cultured from the gastric string in 34 patients (81%), but not in 5 patients due to contamination with oropharyngeal flora. H pylori was cultured from the gastric biopsies obtained at endoscopy in 39 patients (93%). CONCLUSION: The UBT followed by the gastric string test in the case of treatment failure is a valid diagnostic strategy with the aim of determining the post-therapeutic antibiotic resistance of H pylori with little inconvenience to the patient. Upper GI-endoscopy can be avoided in several cases by applying consequently this diagnostic package.