Endoscopic Ultrasound-Guided Biliary Drainage of First Intent With a Lumen-Apposing Metal Stent vs Endoscopic Retrograde Cholangiopancreatography in Malignant Distal Biliary Obstruction: A Multicenter Randomized Controlled Study (ELEMENT Trial).

BACKGROUND & AIMS: Endoscopic ultrasound-guided choledochoduodenostomy with a lumen-apposing metal stent (EUS-CDS) is a promising modality for management of malignant distal biliary obstruction (MDBO) with potential for better stent patency. We compared its outcomes with endoscopic retrograde cholangiopancreatography with metal stenting (ERCP-M). METHODS: In this multicenter randomized controlled trial, we recruited patients with MDBO secondary to borderline resectable, locally advanced, or unresectable peri-ampullary cancers across 10 Canadian institutions and 1 French institution. This was a superiority trial with a noninferiority assessment of technical success. Patients were randomized to EUS-CDS or ERCP-M. The primary end point was the rate of stent dysfunction at 1 year, considering competing risks of death, clinical failure, and surgical resection. Analyses were performed according to intention-to-treat principles. RESULTS: From February 2019 to February 2022, 144 patients were recruited; 73 were randomized to EUS-CDS and 71 were randomized to ERCP-M. The mean (SD) procedure time was 14.0 (11.4) minutes for EUS-CDS and 23.1 (15.6) minutes for ERCP-M (P < .01); 40% of the former was performed without fluoroscopy. Technical success was achieved in 90.4% (95% CI, 81.5% to 95.3%) of EUS-CDS and 83.1% (95% CI, 72.7% to 90.1%) of ERCP-M with a risk difference of 7.3% (95% CI, -4.0% to 18.8%) indicating noninferiority. Stent dysfunction occurred in 9.6% vs 9.9% of EUS-CDS and ERCP-M cases, respectively (P = .96). No differences in adverse events, pancreaticoduodenectomy and oncologic outcomes, or quality of life were noted. CONCLUSIONS: Although not superior in stent function, EUS-CDS is an efficient and safe alternative to ERCP-M in patients with MDBO. These findings provide evidence for greater adoption of EUS-CDS in clinical practice as a complementary and exchangeable first-line modality to ERCP in patients with MDBO. CLINICALTRIALS: gov, Number: NCT03870386.

Fucosyltransferase 2 Mutations Are Associated With a Favorable Clinical Course in Crohn's Disease.

BACKGROUND: Fucosyltransferase 2 (FUT2) participates in intestinal antigen secretion and bacterial adherence. FUT2 homozygous nonsense mutations (FUT2M) and subsequent nonsecretor status is associated with Crohn's disease (CD). The common null allele is rs601338. We assessed the relationship between FUT2M and disease course. METHODS: In consecutive adult CD outpatients, clinical, biochemical, and genetic data were collected at baseline visits. Patients were longitudinally followed over 5 years. The primary outcome analyzed the relationship between FUT2M and rates of CD patients in persistent steroid-free clinical remission requiring neither surgery, biologics, nor immunomodulators. RESULTS: Sixty-two CD patients were recruited. FUT2M homozygotes (rs601338 or any mutation in linkage disequilibrium) were detected in 27% of CD (17/62). Patients with rs601338 mutations had higher rates of the primary outcome (homozygous: 46.6%, heterozygous: 28.0%, wild-type: 5.3%, P=0.02). Similar findings existed for CD patients with homozygous mutations in any single-nucleotide polymorphism for FUT2 (homozygous: 41.2%, heterozygous: 25.9%, wild-type: 5.6%, P=0.04). On multivariable analysis, rs601338 mutation was associated with the primary outcome (odds ratio=3.4, 95% confidence interval: 1.3-8.7, P=0.01), while other parameters were not. Mutation of rs601338 was associated with lower rates of penetrating disease (homozygous: 13.3%, heterozygous: 28.0%, wild-type: 52.6%, P=0.05) and particularly in high-risk patients (homozygous: 0%, heterozygous: 37.5%, wild-type: 83.3%, P=0.01). CONCLUSIONS: FUT2 mutation status is associated with a favorable clinical course in CD. Further confirmatory studies are needed.

Critical appraisal of the mechanisms of gastrointestinal and hepatobiliary infection by COVID-19.

COVID-19 represents a novel infectious disease induced by SARS-CoV-2. It has to date affected 24,240,000 individuals and killed 2,735,805 people worldwide. The highly infectious virus attacks mainly the lung, causing fever, cough, and fatigue in symptomatic patients, but also pneumonia in severe cases. However, growing evidence highlights SARS-CoV-2-mediated extrarespiratory manifestations, namely, gastrointestinal (GI) and hepatic complications. The detection of 1) the virus in the GI system (duodenum, colon, rectum, anal region, and feces); 2) the high expression of additional candidate coreceptors/auxiliary proteins to facilitate the virus entry; 3) the abundant viral angiotensin-converting enzyme 2 receptor; 4) the substantial expression of host transmembrane serine protease 2, necessary to induce virus-cell fusion; 5) the viral replication in the intestinal epithelial cells; and 6) the primarily GI disorders in the absence of respiratory symptoms lead to increased awareness of the risk of disease transmission via the fecal-oral route. The objectives of this review are to provide a brief update of COVID-19 pathogenesis and prevalence, present a critical overview of its GI and liver complications that affect clinical COVID-19 outcomes, clarify associated mechanisms (notably microbiota-related), define whether gut/liver disorders occur more frequently among critically ill patients with COVID-19, determine the impact of COVID-19 on preexisting gut/liver complications and vice versa, and discuss the available strategies for prevention and treatment to improve prognosis of the patients. The novel SARS-CoV-2 can cause gastrointestinal and hepatobiliary manifestations. Metagenomics studies of virobiota in response to SARS-CoV-2 infection are necessary to highlight the contribution of bacterial microflora to COVID-19 phenotype, which is crucial for developing biomarkers and therapeutics.

Cardioprotection via the skin: nociceptor-induced conditioning against cardiac MI in the NIC of time.

Timely reperfusion is still the most effective approach to limit infarct size in humans. Yet, despite advances in care and reduction in door-to-balloon times, nearly 25% of patients develop heart failure postmyocardial infarction, with its attendant morbidity and mortality. We previously showed that cardioprotection results from a skin incision through the umbilicus in a murine model of myocardial infarction. In the present study, we show that an electrical stimulus or topical capsaicin applied to the skin in the same region induces significantly reduced infarct size in a murine model. We define this class of phenomena as nociceptor-induced conditioning (NIC) based on the peripheral nerve mechanism of initiation. We show that NIC is effective both as a preconditioning and postconditioning remote stimulus, reducing infarct size by 86% and 80%, respectively. NIC is induced via activation of skin C-fiber nerves. Interestingly, the skin region that activates NIC is limited to the anterior of the T9-T10 vertebral region of the abdomen. Cardioprotection after NIC requires the integrity of the spinal cord from the region of stimulation to the thoracic vertebral region of the origin of the cardiac nerves but does not require that the cord be intact in the cervical region. Thus, we show that NIC is a reflex and not a central nervous system-mediated effect. The mechanism involves bradykinin 2 receptor activity and activation of PKC, specifically, PKC-α. The similarity of the neuroanatomy and conservation of the effectors of cardioprotection supports that NIC may be translatable to humans as a nontraumatic and practical adjunct therapy against ischemic disease. NEW & NOTEWORTHY This study shows that an electrical stimulus to skin sensory nerves elicits a very powerful cardioprotection against myocardial infarction. This stimulus works by a neurogenic mechanism similar to that previously elucidated for remote cardioprotection of trauma. Nociceptor-induced conditioning is equally potent when applied before ischemia or at reperfusion and has great potential clinically.

Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab, an inhibitor of the p40 subunit of interleukins 12 and 23, is an effective treatment for patients with Crohn's disease (CD). Trough concentrations of tumor necrosis factor (TNF) antagonists and presence of anti-drug antibodies are associated with important clinical and endoscopic outcomes. We investigated associations between trough concentrations of ustekinumab and clinical, biomarker, and endoscopic outcomes of real-world patients with CD. METHODS: We recruited 62 patients with CD who were either refractory or intolerant to TNF antagonists, treated with ustekinumab from April 2014 to September 2015. Patients received 90 mg of ustekinumab subcutaneously at weeks 0, 1, and 2 during induction and 90 mg every 4 or 8 weeks during maintenance. Clinical, biomarker, and endoscopic outcomes, trough concentrations of ustekinumab, and anti-drug antibodies were assessed at both week 10 postinduction therapy and at week 26 or later during maintenance therapy in a prospective longitudinal patient cohort or at week 26 or later during maintenance therapy in a cross-sectional patient cohort. Analysis was performed on data combined from both maintenance cohorts, which had similar outcomes at week 26 or later. A primary analysis determined if ustekinumab drug trough concentrations were associated with clinical response (reduction in Harvey Bradshaw Index score of 3 or greater), clinical remission (Harvey Bradshaw Index score <5), steroid-free clinical remission, biomarker (serum level of C-reactive protein [CRP] or level of fecal calprotectin) reduction, biomarker normalization (serum level of CRP below 5 mg/L or level of fecal calprotectin below 200 µg/g), endoscopic response (simple endoscopic score for CD reduced by 50% or more), or endoscopic remission (simple endoscopic score for CD of 2 or less). RESULTS: At week 26 or beyond, 80.7% of patients had a clinical response, 66.1% were in clinical remission, 50.0% were in steroid-free clinical remission, 58.9% had an endoscopic response, and 19.6% were in endoscopic remission. The mean trough concentration of ustekinumab at this time point was higher in patients with an endoscopic response (4.7 µg/mL) than without (3.8 ug/mL; P = .03). An optimal ustekinumab threshold trough concentration at week 26 or later was found to be 4.5 µg/mL (area under the curve, 0.67). A greater proportion of patients with trough concentrations of ustekinumab above 4.5 µg/mL at week 26 or later had an endoscopic response (75.9%) than did patients with trough concentrations below this level (40.7%; P = .008). Patients with trough concentrations of ustekinumab above 4.5 µg/mL at week 26 or later also had a lower mean level of CRP (12.6 mg/L) than did patients with trough concentrations below this level (mean level of CRP, 23.9 mg/L; P = .04). We did not detect antibodies against ustekinumab in any patient. CONCLUSIONS: Ustekinumab therapy was effective in patients with CD who had not responded to or were intolerant to treatment with a TNF antagonist. Maintenance trough concentrations of ustekinumab above 4.5 µg/mL at 26 weeks or later were associated with biomarker reduction and endoscopic response.

Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.

BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

Childbirth simulation to assess cephalopelvic disproportion and chances for failed labor in a French population.

Reducing failed labor and emergency cesarean section (CS) rates is an important goal. A childbirth simulation tool (PREDIBIRTH software and SIM37 platform) that evaluates a 5-min magnetic resonance imaging (MRI) assessment performed at 37 weeks of gestation was developed to enhance the consulting obstetrician's ability to predict the optimal delivery mode. We aimed to determine the potential value of this childbirth simulation tool in facilitating the selection of an optimal delivery mode for both mother and infant. A retrospective cohort study was performed on all patients referred by their obstetricians to our level 2 maternity radiology department between December 15, 2015 and November 15, 2016, to undergo MRI pelvimetry at approximately 37 weeks of gestation. The childbirth simulation software was employed to predict the optimal delivery mode based on the assessment of cephalopelvic disproportion. The prediction was compared with the actual outcome for each case. Including childbirth simulations in the decision-making process had the potential to reduce emergency CSs, inappropriately scheduled CSs, and instrumental vaginal deliveries by up to 30.1%, 20.7%, and 20.0%, respectively. Although the use of the simulation tool might not have affected the overall CS rate, consideration of predicted birthing outcomes has the potential to improve the allocation between scheduled CS and trial of labor. The routine use of childbirth simulation software as a clinical support tool when choosing the optimal delivery mode for singleton pregnancies with a cephalic presentation could reduce the number of emergency CSs, insufficiently justified CSs, and instrumental deliveries.

Adherence to Objective Therapeutic Monitoring and Outcomes in Patients with Inflammatory Bowel Disease with Adalimumab Treatment. A Real-world Prospective Study.

BACKGROUND AND AIMS: Objective monitoring and effective early treatment using a treat-to-target approach are key to improving therapeutic outcomes in IBD patients. This study aimed to assess adherence to objective monitoring (clinical, biomarkers, and endoscopy) and its impact on clinical outcomes. METHODS: A prospective, multicenter study included consecutive IBD patients starting on adalimumab therapy between January 2019 and December 2020. Disease activity, assessed by the Harvey-Bradshaw index (HBI), partial Mayo, C-reactive protein (CRP), fecal calprotectin (FCAL), and endoscopy were evaluated at adalimumab initiation and 3, 6, 9 and 12 months. Therapeutic drug monitoring, changes in treatment, drug sustainability, and clinical outcomes were assessed. RESULTS: 104 IBD patients were enrolled (78.8% CD, median age 34.3 years, disease duration 9 years). During the 12 months follow-up, high adherence to clinical activity assessment was observed in both CD (81.3%- 87.7%) and UC patients (76.5-90.9%). CRP measurement decreased over time in both CD (37.3%-54.9%) and UC (29.4%-50.0%). The adherence to serial FCAL monitoring was low in CD (22.7-31.3%) and UC patients (17.6-56.0%). UC patients had higher adherence to early endoscopic assessment (<6 months) compared to CD patients (40.9% vs. 21.5%). Adherence to early combined clinical and biomarkers resulted in earlier dose optimization in CD and UC (log-rank<0.001), but drug sustainability was not different. The patients with early combined adherence had a significantly higher clinical remission rate at 1 year compared to non-adherence (70.2% vs. 29.8%, p=0.007) but no significant difference in UC patients. CONCLUSIONS: The adherence to early objective monitoring with combined clinical and biomarkers assessment in IBD patients starting adalimumab therapy led to dose optimization and improved 1-year clinical remission in CD but did not change drug sustainability and clinical remission in UC.

Endoscopist-Directed Propofol as an Adjunct to Standard Sedation: A Canadian Experience.

BACKGROUND: Sedation practices vary widely by region. In Canada, endoscopist-directed administration of a combination of fentanyl and midazolam is standard practice. A minority of cases are performed with propofol. AIMS: To describe the safety of nonanaesthetist administered low-dose propofol as an adjunct to standard sedation. METHODS: This was a single-centre retrospective study of patients having undergone endoscopic procedures with propofol sedation between 2004 and 2012 in a teaching hospital in Montreal. Procedures were performed by gastroenterologists trained in Advanced Cardiovascular Life Support. Sedation was administered by intravenous bolus by a registered nurse, under the direction of the endoscopist. Outcomes of procedures were collected in the context of a retrospective chart review using the hospital's endoscopy database. RESULTS: Of patients undergoing endoscopies at our centre, 4930 patients received propofol as an adjunct to standard sedation with fentanyl and midazolam. Cecal intubation rate for colonoscopies (n = 2921) was 92.0%. Gastroscopies (n = 1614), flexible sigmoidoscopies (n = 28), endoscopic retrograde cholangiopancreatography (n = 331) and percutaneous endoscopic gastrostomy insertion (n = 36) had success rates, defined as successful completion of the procedure within anatomical limits, of 99.0, 96.4, 94.0 and 91.7%, respectively. The average dose of propofol used for each procedure was 34.5 ± 20.8 mg. Fentanyl was used in 67.4% of procedures at an average dose of 94.3 ± 17.5 mcg. Midazolam was used in 92.7% of cases at an average dose of 3.0 ± 0.7 mg. Reversal agents (naloxone or flumazenil) were used in 0.43% of the cases (n = 21). Patients who received propofol were discharged uneventfully within the usual postprocedure recovery time. One patient required sedation-related hospitalization. For patients having received propofol in addition to standard sedation agents, 99.6% experienced no adverse events. There were no mortalities. CONCLUSION: The use of low-dose propofol as an adjunct to fentanyl and midazolam, administered by a registered nurse under the direction of the endoscopist was safe and effective in patients at our centre.

Phenotypic and genotypic characteristics of inflammatory bowel disease in French Canadians: comparison with a large North American repository.

OBJECTIVES: Phenotype characteristics of inflammatory bowel disease (IBD) may differ significantly among ethnic subpopulations. The aim of this study was to characterize the IBD phenotype in French Canadians, the most prominent founder population in North America. METHODS: Using well-characterized phenotype data in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-IBD Genetics Consortium repository on patients with IBD, we compared phenotypic characteristics of 202 French Canadians with those of 1,287 other Caucasian patients. These included diagnosis, anatomical location, disease behavior, extraintestinal manifestations, surgical history, and family history of IBD. RESULTS: French-Canadian patients with Crohn's disease (CD) were less likely to have stricturing disease (11 vs. 21%, P=0.005; odds ratio (OR): 0.45, 95% confidence interval (95% CI): 0.24-0.85). Using a stringent definition of ethnicity (three out of four grandparents being French Canadians, as opposed to self-report, n=148), French Canadians had a tendency toward developing fistulizing CD (37 vs. 28%, P=0.07), and there was an increased prevalence of sacroiliitis among those with IBD (4 vs. 2%, P=0.045). Among French Canadians, the numbers of current smokers in CD (40 vs. 25%, P=0.006) and former smokers in ulcerative colitis (UC) (35 vs. 20%, P=0.03) were significantly higher. The prevalence of one of the three main variants of nucleotide-binding oligomerization domain containing 2 (NOD2) single-nucleotide polymorphisms (SNPs) among French-Canadian CD patients was 43.2%. The 3020insC SNP correlated with small bowel disease in French Canadians (25 [corrected] vs. 0%, P=0.006). CONCLUSIONS: French Canadians show an IBD phenotype profile distinct from other Caucasian IBD populations, with an accentuated association between smoking status and IBD. This unique profile may have implications regarding the need for a different approach to the management of IBD in this population.

Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.

BACKGROUND: Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization. RESULTS: Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable. CONCLUSIONS: In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.

Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin.

BACKGROUND & AIMS: Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohn's disease. METHODS: Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS: Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease. CONCLUSIONS: This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials.

CONTEXT: Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. OBJECTIVE: To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. DESIGN, SETTING, AND PATIENTS: Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. INTERVENTIONS: Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. MAIN OUTCOME MEASURE: Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. RESULTS: For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. CONCLUSION: In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.

Cost-effectiveness of golimumab for the treatment of patients with moderate-to-severe ulcerative colitis in Quebec using a patient level state transition microsimulation.

OBJECTIVE: To conduct cost-effectiveness analyses comparing the addition of golimumab to the standard of care (SoC) for treatment of patients with moderate-to-severe ulcerative colitis (UC) who are refractory to conventional therapies in Quebec (Canada). METHODS: An individual patient state transition microsimulation model was developed to project health outcomes and costs over 10 years, using a payer perspective. The incremental benefit estimates for golimumab were driven by induction response and risk of a flare. Flare risks post-induction were derived for golimumab from the PURSUIT maintenance trial and extension study, while those for SoC were derived from the placebo arms of the Active Ulcerative Colitis Trials (ACT) 1 and 2. Other inputs were derived from multiple sources, including retrospective claims analyses and literature. Costs are reported in 2014 Canadian dollars. A 5% annual discount rate was applied to costs and quality-adjusted life-years (QALYs). RESULTS: Compared with SoC, golimumab was projected to increase the time spent in mild disease or remission states, decrease flare rates, and increase QALYs. These gains were achieved with higher direct medical costs. The incremental cost-effectiveness ratio for golimumab vs SoC was $63,487 per QALY. LIMITATIONS: The long-term flare projections for SoC were based on the data available from the ACT 1 and 2 placebo arms, as data were not available from the PURSUIT maintenance or extension trial. Additionally, the study was limited to only SoC and golimumab, due to the availability of individual patient data to analyze. CONCLUSION: This economic analysis concluded that treatment with golimumab is likely more cost-effective vs SoC when considering cost-effectiveness acceptability thresholds from $50,000-$100,000 per QALY.

Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis.

The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT). We set out to explore its possible role in two other inflammatory diseases: multiple sclerosis (MS) and Crohn's disease (CD). In our cohort of 496 MS trios from the United Kingdom, we observed reduced transmission of the PTPN22 620W allele. The CD sample consisted of 169 trios as well as 249 cases of CD with their 207 matched control subjects collected in the province of Québec, Canada; there was also no evidence of association between the PTPN22 620W allele and susceptibility for CD. Pooled analyses combining our data with published data assessed a total of 1496 cases of MS and 1019 cases of CD but demonstrated no evidence of association with either disease. Given the modest odds ratios of known risk alleles for inflammatory diseases, these analyses do not exclude a role for the PTPN22 allele in susceptibility to CD or MS, but they do suggest that such a putative role would probably be more modest than that reported so far in T1D, RA, SLE, and AIT.

Haplotype-based association analysis of 56 functional candidate genes in the IBD6 locus on chromosome 19.

Evidence from four independent linkage studies and two meta-analyses of genome-wide data support the existence of a locus conferring susceptibility to inflammatory bowel diseases (IBD) in chromosomal region 19p. Identification of a susceptibility allele in this approximately 28.5 Mb region with over 600 genes is a formidable task. To tackle this problem, we undertook two approaches: (1) haplotype-based candidate-gene screen, and (2) evaluation of previously reported associations. For the former, we selected genes with potential implication in IBD pathogenesis based on published functional and expression data, typed SNPs, constructed haplotypes, screened for association in 180 IBD trios, and followed up preliminary associations in 343 IBD patients and 207 control individuals. Overall, we analyzed 465 SNPs, and 260 haplotypes distributed across 56 candidate genes. We found suggestive evidence of association (nominal P<0.01) with four genes (C3, FCER2, IL12RB1, and CRLF1) in a screening stage, but were unable to confirm these preliminary observations at follow-up. In the second approach, we typed four nonsynonymous polymorphisms in genes C3 (R102G and L314P) and ICAM1 (G241R and K469E) in four independent cohorts totaling 2178 IBD cases. We evaluated these data together with previously published reports for three of these variants (C3-Gly102, ICAM1-Arg241, and ICAM1-Glu469), in a meta-analysis. Our pooled meta-analysis provides compelling evidence against association of these variants with disease. Overall, we performed the most comprehensive candidate-gene association study for IBD to date. The information hereby generated constitutes a valuable resource to investigate other common genetic immune diseases, such as celiac disease.

Association of DLG5 R30Q variant with inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal system known as the inflammatory bowel diseases (IBD). Recently, Stoll and colleagues reported a novel finding of genetic variation in the DLG5 gene that is associated with IBD (CD and UC combined). We present here a study of the genetic variation described in that report in two well-powered, independent case-control cohorts and one family-based collection, and confirm the proposed association between IBD and the R30Q variant of DLG5 in two of the three studies. We are, however, unable to replicate the other proposed association to the common haplotype described in Stoll et al and suggest that this other finding could conceivably have been partially a statistical fluctuation and partially a result of LD with the replicated R30Q association. This study provides support for the hypothesis that DLG5 constitutes a true IBD risk factor of modest effect.

The role of ciprofloxacin in prolonging polyethylene biliary stent patency: a multicenter, double-blinded effectiveness study.

Plastic stents are the mainstay of the palliation of malignant jaundice but are complicated by recurrent obstruction. Previous trials have failed to demonstrate any improvement in patency with the use of antibiotics. Patients with malignant jaundice were randomized in a double-blind fashion, after polyethylene stent insertion, to receive ciprofloxacin or placebo. After successful stent decompression, there were 50 patients in the treatment arm and 44 in the placebo. There were 14 (33%) episodes of stent occlusion in the ciprofloxacin group versus 23 (49%) in placebo (chi(2) test, P=0.115). There was no significant difference in patency (log-rank test, P=0.17). There were significantly fewer episodes of cholangitis with ciprofloxacin: 10 (23%) versus 21 (42%) in the placebo (P=0.047). The ciprofloxacin group also demonstrated a significant improvement in the Social Function domain of the SF-36 Quality of Life Survey at 1 month (paired T test, P=0.03). The other domains of the SF-36 were not different, nor was survival (log rank, P=0.80). There is insufficient evidence to show that prophylactic ciprofloxacin can prolong plastic biliary stent patency. The observed trends suggest that ciprofloxacin significantly decreases the incidence of cholangitis and results in improvements in certain aspects of quality of life.

A pharmacokinetic profile of desloratadine in healthy adults, including elderly.

OBJECTIVE: To characterise the pharmacokinetic profile of desloratadine and its main metabolite, 3-hydroxy (3-OH) desloratadine, in a patient population representative of the population studied in the desloratadine clinical efficacy and safety studies, including the elderly. DESIGN: A multicentre, multidose, open-label pharmacokinetic trial. PARTICIPANTS: 113 healthy adult volunteers (57 men, 56 women; 95 White, 18 Black) were enrolled, and 112 completed the study. INTERVENTIONS: A 5mg oral dose of desloratadine once daily for 10 days. MAIN OUTCOME MEASURES: C(max), t(max), t((1/2)) and AUC(24h). RESULTS: Steady-state plasma concentrations were attained by day 7. Peak plasma concentrations (C(max)) of desloratadine (mean 3.98 micro g/L) and 3-OH desloratadine (mean 1.99 micro g/L) were reached at a mean of 3.17 and 4.76 hours (t(max)), respectively, after administration. The area under the plasma concentration-time curve from 0 to 24 hours (AUC(24h)) was 56.9 micro g/L x h for desloratadine and 32.3 micro g/L x h for 3-OH desloratadine. The mean half-lives (t((1/2))) of desloratadine and 3-OH desloratadine were 26.8 and 36 hours, respectively. There were no clinically relevant differences in the calculated pharmacokinetic parameters of desloratadine when participants were stratified into 3 age groups (19 to 45, 46 to 64 and 65 to 70 years). Treatment-emergent adverse events occurred in 31 of the 113 participants (3 of the 17 aged >or=65 years reported adverse events). All adverse events were mild to moderate in severity, and none resulted in discontinuation of treatment. There were no consistent clinically relevant changes in blood pressure, pulse, oral body temperature or electrocardiogram evaluations and no reports of syncope or sedation. CONCLUSION: Daily administration of desloratadine 5mg is well tolerated. The 27-hour half-life of desloratadine permits once daily administration. No dosage adjustment of desloratadine is required in the elderly.

Effect of race and sex on single and multiple dose pharmacokinetics of desloratadine.

OBJECTIVE: This study was designed to characterise the single and multiple dose pharmacokinetic profile of desloratadine, a new antihistamine, and its main metabolite, 3-hydroxy (3-OH) desloratadine, in healthy volunteers differing in sex and race. DESIGN: An open-label, parallel-group, single- and multiple-dose pharmacokinetic trial. INTERVENTION: A single 7.5mg oral tablet of desloratadine on day 1, followed by 7.5mg daily doses on days 4 to 17. PARTICIPANTS: 48 healthy, nonsmoking volunteers (12 White men, 12 Black men, 12 White women, 12 Black women). MAIN OUTCOME MEASURES: AUC(24h) and C(max) determined from serial blood samples of desloratadine and 3-OH desloratadine. RESULTS: There were no clinically relevant differences between men and women or Black participants and White participants for desloratadine and 3-OH desloratadine maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve (AUC). Following multiple doses, the geometric mean C(max) was 5.17 microg/L in men, 5.68 microg/L in women, 5.87 microg/L in Black participants and 5.00 microg/L in White participants; the corresponding AUC from 0 to 24 hours (AUC(24h)) values were 77.9, 80.0, 90.6 and 68.8 micro g/L x h. Corresponding 3-OH desloratadine geometric mean C(max) values were 1.93, 2.79, 2.20 and 2.45 microg/L, and the AUC(24h) values were 32.1, 47.5, 37.1 and 41.1 microg/L. h. CONCLUSIONS: Oral administration of multiple doses of desloratadine 7.5mg, a dose 50% higher than the recommended 5mg clinical dose, was well tolerated by healthy adults differing in sex and race. Comparison of the C(max) and AUC values following 14 days of treatment with desloratadine indicates that no dosage adjustment is needed on the basis of sex or race.