10-year follow-up results of the European Achalasia Trial: a multicentre randomised controlled trial comparing pneumatic dilation with laparoscopic Heller myotomy.

OBJECTIVE: As achalasia is a chronic disorder, long-term follow-up data comparing different treatments are essential to select optimal clinical management. Here, we report on the 10-year follow-up of the European Achalasia Trial comparing endoscopic pneumodilation (PD) with laparoscopic Heller myotomy (LHM). DESIGN: A total of 201 newly diagnosed patients with achalasia were randomised to either a series of PDs (n=96) or LHM (n=105). Patients completed symptom (Eckardt score) and quality-of-life questionnaires, underwent functional tests and upper endoscopy. Primary outcome was therapeutic success defined as Eckardt score <3 at yearly follow-up. Secondary outcomes were the need for retreatment, lower oesophageal sphincter pressure, oesophageal emptying, gastro-oesophageal reflux and the rate of complications. RESULTS: After 10 years of follow-up, LHM (n=40) and PD (n=36) were equally effective in both the full analysis set (74% vs 74%, p=0.84) and the per protocol set (74% vs 86%, respectively, p=0.07). Subgroup analysis revealed that PD was superior to LHM for type 2 achalasia (p=0.03) while there was a trend, although not significant (p=0.05), that LHM performed better for type 3 achalasia. Barium column height after 5 min at timed barium oesophagram was significantly higher for patients treated with PD compared with LHM, while other parameters, including gastro-oesophageal reflux, were not different. CONCLUSIONS: PD and LHM are equally effective even after 10 years of follow-up with limited risk to develop gastro-oesophageal reflux. Based on these data, we conclude that PD and LHM can both be proposed as initial treatment of achalasia.

Immunoglobulin A Glycosylation Differs between Crohn's Disease and Ulcerative Colitis.

Inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), are chronic and relapsing inflammations of the digestive tract with increasing prevalence, yet they have unknown origins or cure. CD and UC have similar symptoms but respond differently to surgery and medication. Current diagnostic tools often involve invasive procedures, while laboratory markers for patient stratification are lacking. Large glycomic studies of immunoglobulin G and total plasma glycosylation have shown biomarker potential in IBD and could help determine disease mechanisms and therapeutic treatment choice. Hitherto, the glycosylation signatures of plasma immunoglobulin A, an important immunoglobulin secreted into the intestinal mucin, have remained undetermined in the context of IBD. Our study investigated the associations of immunoglobulin A1 and A2 glycosylation with IBD in 442 IBD cases (188 CD and 254 UC) and 120 healthy controls by reversed-phase liquid chromatography electrospray-ionization mass spectrometry of tryptic glycopeptides. Differences of IgA O- and N-glycosylation (including galactosylation, bisection, sialylation, and antennarity) between patient groups were associated with the diseases, and these findings led to the construction of a statistical model to predict the disease group of the patients without the need of invasive procedures. This study expands the current knowledge about CD and UC and could help in the development of noninvasive biomarkers and better patient care.

Peroral Endoscopic Myotomy for the Treatment of Esophageal Diverticula: A Systematic Review and Meta-analysis.

BACKGROUND: There is limited evidence on the efficacy of peroral endoscopic myotomy (POEM) in patients with esophageal diverticula. AIMS: This meta-analysis aimed to assess the efficacy and safety profile of POEM in patients with Zenker (ZD) and epiphrenic diverticula. METHODS: With a literature search through August 2020, we identified 12 studies (300 patients) assessing POEM in patients with esophageal diverticula. The primary outcome was treatment success. Results were expressed as pooled rates and 95% confidence intervals. RESULTS: Pooled rate of technical success was 95.9% (93.4%-98.3%) in ZD patients and 95.1% (88.8%-100%) in patients with epiphrenic diverticula. Pooled rate of treatment success was similar for ZD (90.6%, 87.1%-94.1%) and epiphrenic diverticula (94.2%, 87.3%-100%). Rates of treatment success were maintained at 1 year (90%, 86.4%-97.4%) and 2 years (89.6%, 82.2%-96.9%) in ZD patients. Pooled rate of symptom recurrence was 2.6% (0.9%-4.4%) in ZD patients and 0% in patients with epiphrenic diverticula. Pooled rates of adverse events and severe adverse events were 10.6% (4.6%-16.6%) and 3.5% (0%-7.4%) in ZD and 8.4% (0%-16.8%) and 8.4% (0%-16.8%) in epiphrenic diverticula, respectively. CONCLUSION: POEM represents an effective and safe therapy for the treatment of esophageal diverticula.

Comparative efficacy of first-line therapeutic interventions for achalasia: a systematic review and network meta-analysis.

BACKGROUND: Several interventions with variable efficacy are available as first-line therapy for patients with achalasia. We assessed the comparative efficacy of different strategies for management of achalasia, through a network meta-analysis combining direct and indirect treatment comparisons. METHODS: We identified six randomized controlled trials in adults with achalasia that compared the efficacy of pneumatic dilation (PD; n = 260), laparoscopic Heller myotomy (LHM; n = 309), and peroral endoscopic myotomy (POEM; n = 176). Primary efficacy outcome was 1-year treatment success (patient-reported improvement in symptoms based on validated scores); secondary efficacy outcomes were 2-year treatment success and physiologic improvement; safety outcomes were risk of gastroesophageal reflux disease (GERD), severe erosive esophagitis, and procedure-related serious adverse events. We performed pairwise and network meta-analysis for all treatments, and used GRADE criteria to appraise quality of evidence. RESULTS: Low-quality evidence, based primarily on direct evidence, supports the use of POEM (RR [risk ratio], 1.29; 95% confidence intervals [CI], 0.99-1.69), and LHM (RR, 1.18 [0.96-1.44]) over PD for treatment success at 1 year; no significant difference was observed between LHM and POEM (RR 1.09 [0.86-1.39]). The incidence of severe esophagitis after POEM, LHM, and PD was 5.3%, 3.7%, and 1.5%, respectively. Procedure-related serious adverse event rate after POEM, LHM, and PD was 1.4%, 6.7%, and 4.2%, respectively. CONCLUSIONS: POEM and LHM have comparable efficacy, and may increase treatment success as compared to PD with low confidence in estimates. POEM may have lower rate of serious adverse events compared to LHM and PD, but higher rate of GERD.

Prevalence and Predictors of Reduced Bone Density in Child and Adolescent Patients With Crohn's Disease.

Reduced bone mineral density (BMD) has broadly been found to be associated with inflammatory bowel disease across a number of geographical locations and cultures. We aimed to estimate the prevalence of reduced BMD and identify clinical predictors in a cohort of Crohn's disease patients (CD) in Saudi Arabia. We conducted a retrospective study involving children and adolescents with CD between 2013 and 2018. BMD was evaluated using dual-energy X-ray absorptiometry scans of the spine and body. A multivariate analysis was performed for the detection of predictors of low BMD. Sixty-four patients were enrolled. The median age was 16 years (range, 8-19 years) and 55% of patients were males. Total body BMD scanning identified 25 patients (39%) with osteoporosis. Twenty patients (31.3%) were found to have z scores consistent with osteopenia. A multivariate regression analysis identified a low weight-for-age z score (B coefficient = 0.347, 95% confidence interval [CI] = 0.211-0.482, p < 0.001 for Spine BMD and B coefficient = 0.321, 95% CI = 0.170-0.472, p < 0.001 for total body BMD), a low height-for-age z score (B coefficient = 0.187, 95% CI = 0.035-0.338, p = 0.017 for spine BMD and B coefficient = 0.0.258, 95% CI = 0.089-0.427, p = 0.004 for total body BMD), a low 25-hyroxyvitamin D level (B coefficient = 0.026, 95% CI = 0.013-0.038, p < 0.001 for spine BMD and B coefficient = 0.016, 95% CI = 0.002-0.031, p = 0.026 for total body BMD), and a higher number of corticosteroid induction courses (B coefficient = -0.567, 95% CI = -0.923 to -0.212, p = 0.003 for spine BMD and B coefficient = -0.566, 95% CI = 0.963-0.169, p = 0.007 for total body BMD) as predictors of low BMD. In the spine BMD analysis, older age at the time of presentation was identified as a significant predictor for low bone density (B coefficient = 0.254, 95% CI = 0.141-0.368, p < 0.001). In conclusion, Saudi Arabian children and adolescents with CD have a high prevalence rate of low bone density compared to Western populations. Several clinical characteristics are identified as significant predictors for low BMD.

Genetics and epigenetics of IBD.

Inflammatory bowel diseases (IBD) are chronic intermittent inflammatory disorders of the gastrointestinal tract of unknown etiology but a clear genetic predisposition. Prompted by the first investigations on IBD families and twins, the genetic and epigenetic studies have produced an unprecedented amount of information in comparison with other immune-mediated or complex diseases. New inflammatory pathways and possible mechanisms of action have been disclosed, potentially leading to new-targeted therapy. However, the identification of genetic markers due to the great disease heterogeneity and the overwhelming contribution of environmental risk factors has not modified yet the disease management. The possibility for the future of a better prediction of disease course, response to therapy and therapy-related adverse events may allow a more efficient and personalized strategy. This review will focus on more recent discoveries that may potentially be of relevance in daily clinical practice.

Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: Causes of inflammatory bowel diseases are not well understood and the most prominent forms, Crohn's disease (CD) and ulcerative colitis (UC), are sometimes hard to distinguish. Glycosylation of IgG has been associated with CD and UC. IgG Fc-glycosylation affects IgG effector functions. We evaluated changes in IgG Fc-glycosylation associated with UC and CD, as well as with disease characteristics in different patient groups. METHODS: We analyzed 3441 plasma samples obtained from 2 independent cohorts of patients with CD (874 patients from Italy and 391 from the United States) or UC (1056 from Italy and 253 from the US and healthy individuals [controls]; 427 in Italy and 440 from the United States). IgG Fc-glycosylation (tryptic glycopeptides) was analyzed by liquid chromatography coupled to mass spectrometry. We analyzed associations between disease status (UC vs controls, CD vs controls, and UC vs CD) and glycopeptide traits, and associations between clinical characteristics and glycopeptide traits, using a logistic regression model with age and sex included as covariates. RESULTS: Patients with CD or UC had lower levels of IgG galactosylation than controls. For example, the odds ratio (OR) for IgG1 galactosylation in patients with CD was 0.59 (95% confidence interval [CI], 0.51-0.69) and for patients with UC was 0.81 (95% CI, 0.71-0.92). Fucosylation of IgG was increased in patients with CD vs controls (for IgG1: OR, 1.27; 95% CI, 1.12-1.44), but decreased in patients with UC vs controls (for IgG23: OR, 0.72; 95% CI, 0.63-0.82). Decreased galactosylation associated with more severe CD or UC, including the need for surgery in patients with UC vs controls (for IgG1: OR, 0.69; 95% CI, 0.54-0.89) and in patients with CD vs controls (for IgG23: OR, 0.78; 95% CI, 0.66-0.91). CONCLUSIONS: In a retrospective analysis of plasma samples from patients with CD or UC, we associated levels of IgG Fc-glycosylation with disease (compared to controls) and its clinical features. These findings could increase our understanding of mechanisms of CD and UC pathogenesis and be used to develop diagnostics or guide treatment.

Plasma N-Glycan Signatures Are Associated With Features of Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Biomarkers are needed for early detection of Crohn's disease (CD) and ulcerative colitis (UC) or to predict patient outcomes. Glycosylation is a common and complex posttranslational modification of proteins that affects their structure and activity. We compared plasma N-glycosylation profiles between patients with CD or UC and healthy individuals (controls). METHODS: We analyzed the total plasma N-glycomes of 2635 patients with inflammatory bowel diseases and 996 controls by mass spectrometry with a linkage-specific sialic acid derivatization technique. Plasma samples were acquired from 2 hospitals in Italy (discovery cohort, 1989 patients with inflammatory bowel disease [IBD] and 570 controls) and 1 medical center in the United States (validation cohort, 646 cases of IBD and 426 controls). Sixty-three glycoforms met our criteria for relative quantification and were extracted from the raw data with the software MassyTools. Common features shared by the glycan compositions were combined in 78 derived traits, including the number of antennae of complex-type glycans and levels of fucosylation, bisection, galactosylation, and sialylation. Associations of plasma N-glycomes with age, sex, CD, UC, and IBD-related parameters such as disease location, surgery and medication, level of C-reactive protein, and sedimentation rate were tested by linear and logistic regression. RESULTS: Plasma samples from patients with IBD had a higher abundance of large-size glycans compared with controls, a decreased relative abundance of hybrid and high-mannose structures, lower fucosylation, lower galactosylation, and higher sialylation (α2,3- and α2,6-linked). We could discriminate plasma from patients with CD from that of patients with UC based on higher bisection, lower galactosylation, and higher sialylation (α2,3-linked). Glycosylation patterns were associated with disease location and progression, the need for a more potent medication, and surgery. These results were replicated in a large independent cohort. CONCLUSIONS: We performed high-throughput analysis to compare total plasma N-glycomes of individuals with vs without IBD and to identify patterns associated with disease features and the need for treatment. These profiles might be used in diagnosis and for predicting patients' responses to treatment.

Computed tomography or contrast-enhanced ultrasonography for follow-up of liver metastases after Cyberknife therapy?: A prospective pilot study.

OBJECTIVES: Contrast-enhanced ultrasonography (CEUS) allows the study of vascularization of secondary liver lesions. The Cyberknife (Accuray, Inc, Sunnyvale, CA) is a therapeutic method that allows a tumor target to be subjected to a high radiant dose gradient. This prospective pilot study aimed to demonstrate the concordance of CEUS versus contrast-enhanced computed tomography (CECT) in determining the stability or disease progression of secondary liver lesions after treatment with the Cyberknife. METHODS: Twenty-four patients were consecutively enrolled, and 3 different operators evaluated the CEUS images and the intermodality concordance with CECT. All patients received CEUS at 1 and 2 months after the Cyberknife therapy. The intermodality agreement was evaluated by the Cohen κ coefficient and a multivariate analysis according to the method of Janson and Olsson (Educ Psychol Meas 2001; 61:277-289). RESULTS: Forty secondary liver lesions were detected and treated. Forty-one CECT and 51 CEUS examinations were performed without any adverse events in the 24 patients. The intermodality agreement rates, calculated for the operators as Cohen κ values, were κ = 1.00, 0.881, and 0.767, respectively. The multivariate analysis of intermodality agreement showed an almost perfect value (ι = 0.841). CONCLUSIONS: This pilot study found excellent diagnostic correspondence between CEUS and CECT in the evaluation of local disease stability or progression after Cyberknife therapy in liver metastases. These findings suggest that CEUS could play an important role in the surveillance of these patients because of its high accuracy and reproducibility, thus reducing the need for CECT.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Prospective Evaluation of Liver Stiffness Using Transient Elastography in Alcoholic Patients Following Abstinence.

AIMS: Fibroscan® is a non-invasive method to evaluate liver stiffness (LS), however, its accuracy in alcohol-related liver diseases (ALD) especially with respect to active or stopped alcohol drinking is largely unknown. We prospectively evaluated the LS changes in patients with ALD following alcohol withdrawal. METHODS: Sixty-four patients were evaluated by FibroScan® and lab tests at baseline and after 4 weeks of abstinence. RESULTS: At baseline, 21 patients (33%) had an abnormal LS (> 7 kPa) and 32 patients (50%) had abnormal liver function tests. More specifically, 3 and 11 subjects had a LS higher than 9.6 kPa and 12.5 kPa, respectively. The LS significantly declined in abstinent from 9.2 ± 10.1 (M±SD) at the baseline to 6.9 ± 6.1 kPa at 4 weeks (P = 0.03), respectively, while did not change significantly in drinkers. In addition, 80% of abstainers had a significant LS reduction (-2.6 ± 5.5 kPa), compared to drinkers (2.2 ± 3.6 kPa) (P = 0.004). After 6 months, 27 patients accepted a further evaluation: 22 abstinent and 5 relapsed to drink. At the final evaluation, only 4 out of 22 abstainers had still a LS higher than 7 kPa. CONCLUSIONS: During active drinking LS is probably overestimated by Fibroscan® in ALD, since 1 month after abstinence it is dramatically reduced, especially in subjects with baseline values higher than 7 kPa. SHORT SUMMARY: We prospectively evaluated liver stiffness by Fibroscan® in patients with alcohol-related liver disease at baseline and following abstinence. After 1 month of abstinence, the LS is dramatically reduced, especially when values are greater than 7 kPa and transaminase elevated at baseline.

Long-term results of the European achalasia trial: a multicentre randomised controlled trial comparing pneumatic dilation versus laparoscopic Heller myotomy.

OBJECTIVE: Achalasia is a chronic motility disorder of the oesophagus for which laparoscopic Heller myotomy (LHM) and endoscopic pneumodilation (PD) are the most commonly used treatments. However, prospective data comparing their long-term efficacy is lacking. DESIGN: 201 newly diagnosed patients with achalasia were randomly assigned to PD (n=96) or LHM (n=105). Before randomisation, symptoms were assessed using the Eckardt score, functional test were performed and quality of life was assessed. The primary outcome was therapeutic success (presence of Eckardt score ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for re-treatment, lower oesophageal sphincter pressure, oesophageal emptying and the rate of complications. RESULTS: In the full analysis set, there was no significant difference in success rate between the two treatments with 84% and 82% success after 5 years for LHM and PD, respectively (p=0.92, log-rank test). Similar results were obtained in the per-protocol analysis (5-year success rates: 82% for LHM vs. 91% for PD, p=0.08, log-rank test). After 5 years, no differences in secondary outcome parameter were observed. Redilation was performed in 24 (25%) of PD patients. Five oesophageal perforations occurred during PD (5%) while 12 mucosal tears (11%) occurred during LHM. CONCLUSIONS: After at least 5 years of follow-up, PD and LHM have a comparable success rate with no differences in oesophageal function and emptying. However, 25% of PD patients require redilation during follow-up. Based on these data, we conclude that either treatment can be proposed as initial treatment for achalasia. TRIAL REGISTRATION NUMBERS: Netherlands trial register (NTR37) and Current Controlled Trials registry (ISRCTN56304564).

Randomised controlled trial of mesalazine in IBS.

OBJECTIVE: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. DESIGN: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. RESULTS: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. CONCLUSIONS: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. TRIAL REGISTRATION NUMBER: ClincialTrials.gov number, NCT00626288.

Vitamin D regulates the tight-junction protein expression in active ulcerative colitis.

OBJECTIVE: Epithelial barrier function is primarily regulated by the tight-junction proteins. Ulcerative colitis (UC) is characterized by Th2 immune response with inflammation and epithelial barrier dysfunction, including an elevation of claudin-2 protein function. Recent studies support an important role of vitamin D in the pathogenesis as well as potential therapy of IBD. Vitamin D deficiency is in fact common in patients with IBD. The aim of the study was to determine whether vitamin D could affect IL-13 and IL-6 levels, and regulate the activity of tight-junction proteins. Claudin-1, -2, -4, and -7 in the inflamed and non-inflamed colonic mucosa of UC patients. MATERIAL AND METHODS: Biopsies from inflamed and non-inflamed tract of colon and rectum from the same active UC patients were cultured with1,25(OH)2D3. IL-13, IL-6 and the tight-junction proteins level were determined. RESULTS: Claudin-1 and claudin-2 proteins were up-regulated in active UC. The treatment with 1,25(OH)2D3 decreases the claudin-1 and claudin-2 protein levels in both inflamed and non-inflamed tract. Claudin-4 and claudin-7 proteins were down-regulated and their levels increase after incubation with the 1,25(OH)2D3. When the biopsies were incubated with 1,25(OH)2D3, a decrease in IL-13 and IL-6 levels was registered. CONCLUSIONS: Our results, indicating the inhibition of cytokine levels and the regulation of claudin-2, claudin-4, and claudin-7 by 1,25(OH)2D3, suggest that vitamin D may represent a potential therapeutic agent for the treatment of active UC.

Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53 × 10(-8), 11q13 near PRDX5, p(rs694739) = 3.71 × 10(-09), 22q11 at YDJC, p(rs181359) = 8.02 × 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99 × 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.

Oral prolonged release beclomethasone dipropionate and prednisone in the treatment of active ulcerative colitis: results from a double-blind, randomized, parallel group study.

OBJECTIVES: Double-blind study comparing efficacy and safety of the topically acting corticosteroid beclomethasone dipropionate (BDP) to prednisone (PD) in patients with active, mild-to-moderate ulcerative colitis (UC). METHODS: Overall, 282 patients were randomized to receive BDP-prolonged release tablets 5 mg once daily for 4 weeks and then every other day for an additional 4 weeks or oral PD 40 mg once daily for the initial 2 weeks tapered of 10 mg every 2 weeks during the 8-week study period. Efficacy end point was the non-inferiority of BDP vs. PD in terms of Disease Activity Index (DAI) score <3 or reduction by at least 3 points for patients with a baseline DAI ≥7 at week 4. Safety end point was the proportion of patients with steroid-related adverse events (AEs) and cortisol <150 nmol/l at week 4. RESULTS: DAI response rates at week 4 were 64.6% and 66.2% with BDP and PD, respectively, demonstrating non-inferiority of BDP vs. PD (delta: -1.56; 95% confidence interval (CI) -13.00-9.88, P=0.78). Patients with steroid-related AEs and cortisol <150 nmol/l at week 4 were 38.7% in the BDP group and 46.9% in the PD group (P=0.17 between groups). No safety signals were observed in both the groups. CONCLUSIONS: BDP was non-inferior to PD in the treatment of active UC, with a good safety profile in both the groups.

Smoking as an independent determinant of Barrett's esophagus and, to a lesser degree, of reflux esophagitis.

PURPOSE: To evaluate the role of smoking in Barrett's esophagus (BE) and erosive esophagitis (E) compared to endoscopic controls with no BE or E. Smoking is considered a cause of both BE and E, but results on this topic are quite controversial. METHODS: Patients with BE (339), E (462) and controls (619: 280 with GERD (gastroesophageal reflux disease)-negative and 339 with GERD-positive anamnesis) were recruited in 12 Italian endoscopy units. Data were obtained from structured questionnaires. RESULTS: Among former smokers, a remarkable upward linear trend was found in BE for all smoking-related predictors. In particular, having smoked for more than 32 years increased the risk more than two times (OR 2.44, 95 % CL 1.33-4.45). When the analysis was performed in the subgroup of subjects with GERD-negative anamnesis, the risk of late quitters (<9 years) passed from OR 2.11 (95 % CL 1.19-3.72) to OR 4.42 (95 % CL 1.52-12.8). A noticeably positive dose-response relationship with duration was seen also among current smokers. As regards E, no straightforward evidence of association was detected, but for an increased risk of late quitters (OR 1.84, 95 % CL 1.14-2.98) in former smokers and for early age at starting (OR 3.63, 95 % CL 1.19-11.1) in GERD-negative current smokers. CONCLUSIONS: Smoking seems to be an independent determinant of BE and, to a lesser degree, of E. The elevation in risk is independent from GERD and is already present in light cigarette smokers. Smoking cessation may reduce, but not remove this risk.