Kian Keyashian

Effect of alvimopan and codeine on gastrointestinal transit: A randomized controlled study

UNLABELLED background & aims: Opiate bowel dysfunction is a significant clinical problem. Our aim was to evaluate the ability of a peripheral mu-opioid antagonist, alvimopan, to reverse the effect of codeine on gastric, small-bowel, and colonic transit time in healthy volunteers. METHODS Seventy-four healthy participants (43 women) were randomized in a double-blind, placebo-controlled manner to 1 of 4 groups: alvimopan 12 mg twice daily in the presence and absence of codeine sulfate 30 mg 4 times/day, or codeine or placebo alone. Gastric emptying, small-bowel, and colonic transit were measured by scintigraphy using a 99m-labeled technetium egg meal and 111-labeled indium charcoal delivered to the proximal colon via a delayed-release capsule. The primary end points for colonic transit were geometric center of the colonic counts at 24 hours and time for 50% ascending colon emptying. Analysis of covariance was used to assess the significance of the primary and secondary end points. RESULTS Codeine delayed gastric, small-bowel, proximal, and overall colonic transit (P < .05). Alvimopan reversed codeines effect on small bowel and colon (ascending colon and overall colonic transit). Alvimopan also accelerated overall colonic transit compared with placebo. Thus, the mean colonic geometric center at 24 hours was 2.33 with placebo/placebo, 3.25 with alvimopan/placebo (P < .05), 1.5 with placebo/codeine (P < .05), and 2.63 with alvimopan/codeine. Alvimopan did not reverse codeines delay of gastric emptying. CONCLUSIONS Alvimopan reverses codeines inhibitory effect on small-bowel and colon transit and has potential for treatment of opiate bowel dysfunction. Alvimopan alone accelerates colonic transit, suggesting that mu-opiate mechanisms participate in the physiologic control of colonic transit.

Natalizumab in Crohn's disease: results from a US tertiary inflammatory bowel disease center.

Background:Natalizumab is an efficacious agent for the induction and maintenance of remission in patients with Crohn’s disease (CD) who have failed anti–tumor necrosis factor (TNF) agents. We aimed to assess the efficacy and safety of natalizumab outside of clinical trial at a US tertiary center. Methods:Retrospective case review of patients with CD receiving natalizumab. Results:Forty-nine patients with CD (28 women; median age, 33 years) receiving natalizumab from April 2008 to November 2011 were identified. Median duration of disease was 180 months (range, 36–576 months); 40 patients had ileocolonic disease, 1 had ileal disease, and 8 had colonic disease. Twenty-one patients had penetrating disease, and 28 had a history of CD-related surgical treatment. Forty-seven patients previously failed treatment with at least 1 anti-TNF agent. Median duration of natalizumab treatment was 7 months (interquartile range, 3–21.5 months). Twenty-four patients (49%) were continuing natalizumab at the time of this review, and 25 discontinued treatment because of the lack of response, side effects, or positive JC virus antibody. Seventeen patients (35%) successfully continued treatment with natalizumab for longer than 12 months, and nonpenetrating disease phenotype was identified as a predictor of longer response (compared with penetrating phenotype; P = 0.013). Nine patients (18.4%) experienced adverse effects, 5 of which were serious, but no case of progressive multifocal leukoencephalopathy occurred. Conclusions:This is the largest series of natalizumab-treated patients with CD. Our results show that natalizumab is an efficacious and safe treatment agent for patients refractory to anti-TNF agents and that nonpenetrating disease phenotype has more durable response over time.

Natural history of acute upper GI bleeding due to tumours: Short-term success and long-term recurrence with or without endoscopic therapy

Scant information is available regarding patients with upper gastrointestinal bleeding (UGIB) from tumours.

Initial surgical management of ulcerative colitis in the biologic era

BACKGROUND:The initial minimum operation for ulcerative colitis is a total abdominal colectomy. Healthy patients may undergo proctectomy at the same time; however, for ill patients, proctectomy is delayed. Since the introduction of biologic medications in 2005, ulcerative colitis medical management has changed dramatically. OBJECTIVE:We examined how operative management for ulcerative colitis has changed from the prebiologic to biologic eras. DESIGN:We conducted a retrospective review of data on patients with ulcerative colitis who were included in the Nationwide Inpatient Sample database. SETTINGS:This study was conducted at a single university. PATIENTS:A total of 1,547,852 patients with ulcerative colitis who were admitted to a US hospital from 1991 to 2011 were included in the study. MAIN OUTCOME MEASURES:We examined patients whose initial operation consisted of total abdominal colectomy without proctectomy versus a total proctocolectomy with or without a pouch. We also examined which operation was done at the time of the construction of an ileoanal pouch. Patients who underwent colectomy and pouch construction in the same hospitalization were compared with those who received pouch formation at a subsequent hospitalization. RESULTS:Ulcerative colitis–related admissions rose by 170% during the years examined, and the number of patients who required total abdominal colectomy increased by 44%. Total abdominal colectomy increased by 15%, as opposed to total proctocolectomy (p < 0.001). Pouch construction at a subsequent operation increased by 16% (p = 0.002). Since 2008, total abdominal colectomy has surpassed total proctocolectomy as the most common initial surgical intervention for ulcerative colitis. LIMITATIONS:The Nationwide Inpatient Sample is a retrospective database, and we were limited to examining the variables within it. CONCLUSIONS:Total abdominal colectomy is currently the most common initial operation for patients with ulcerative colitis, and an ileoanal pouch is more frequently constructed at a subsequent hospitalization. These trends coincide with the initiation of biologic treatments and may imply that patients are acutely ill at the time of initial operation. Alternately, there may be surgeon-perceived bias of increased surgical risk or a shift in care to specialized surgeons for pouch construction.

Prevalence of Antibodies Against JC Virus in Patients With Refractory Crohn’s Disease and Effects of Natalizumab Therapy

BACKGROUND & AIMS Natalizumab, a humanized antibody against the α4 integrin subunit, effectively induces and maintains remission in patients with Crohns disease (CD) refractory to conventional treatments. Progressive multifocal leukoencephalopathy is a rare but fatal brain infection caused by John Cunningham (JC) virus and has been associated with natalizumab use. We assessed the prevalence of and risk factors for antibodies to JC virus in serum of patients with refractory CD who were candidates for, or already were receiving, natalizumab. We also assessed the effects of natalizumab treatment of these patients. METHODS In a retrospective study, we analyzed clinical charts from 191 patients with CD (74 males; mean age, 38.7 y; mean duration of disease, 14.9 y) tested for serum JC virus antibody from December 2012 through May 2014 at 2 medical centers in the United States. We calculated JC virus antibody prevalence and compared the characteristics of patients who tested negative vs those who tested positive, to identify risk factors. We also assessed the rate of subsequent natalizumab use, surgery, and seroconversion during natalizumab therapy. RESULTS A total of 129 of the patients (67.5%) tested positive for serum JC virus antibody. Multivariate analysis showed that past use of thiopurine was a risk factor for testing positive for JC virus antibody (odds ratio, 7.8; 95% confidence interval, 2.0-30.4; P = .003). Twenty-two of the patients who tested negative for JC virus antibody (35.5%) and 16 of the 129 patients who tested positive (12.4%) had been treated with natalizumab. Cox regression analysis determined that natalizumab use was the only factor associated with avoiding subsequent surgery (hazard ratio, 0.23; 95% confidence interval, 0.06-0.98). Seroconversion (from testing negative to positive for JC virus antibody) occurred in 1 of the 22 patients (4.5%) who initially tested negative during natalizumab therapy. CONCLUSIONS The prevalence of CD patients exposed to JC virus is comparable with that of the general population. In this retrospective study, prior thiopurine use was associated with an increased risk for testing positive for JC virus antibody. Natalizumab use reduced the risk of subsequent surgery.

Barrett's esophagus in Latinos undergoing endoscopy for gastroesophageal reflux disease symptoms.

Previous studies comparing the prevalence of Barretts esophagus in Latinos and non-Latino whites are inconsistent. The aim of the study is to compare the prevalence of Barretts esophagus in Latinos and non-Latino whites and to determine risk factors associated with Barretts esophagus. Between March 2005 and January 2009, consecutive Latino and non-Latino white patients who underwent endoscopy for primary indication for symptoms of gastroesophageal reflux disease were identified by examining the internal endoscopy database at Los Angeles County + USC Medical Center. Barretts esophagus was defined by columnar-lined distal esophagus on endoscopy confirmed by intestinal metaplasia on histology. Clinical features and endoscopic findings were retrospectively reviewed. The mean age of the 663 patients was 50 ± 12 years, 30% were male, and 92% were Latino. Compared with non-Latino whites, Latinos had more females (72% vs. 46%; P = 0.0001) and more Helicobacter pylori infection (53% vs. 24%; P = 0.003) but less tobacco use (7% vs. 17%; P = 0.01). Overall, 10% (68/663) of all patients had Barretts esophagus whereas the prevalence was 10% (62/611) among the Latinos and 12% (6/52) among the non-Latino whites (OR 0.9, 95% CI 0.4-2.1; P = 0.75). One patient in the Latino group had high-grade dysplasia. On multivariate analysis, male gender (AOR 2.3, 95% CI 1.4-4.1; P = 0.002), diabetes (AOR 2.2, 95% CI 1.1-4.5; P = 0.03), and age ≥55 years (AOR 2.2, 95% CI 1.3-3.8; P = 0.006) were independently associated with Barretts esophagus; Latino ethnicity remained nonsignificant (AOR 1.1, 95% CI 0.4-2.7; P = 0.88). In Latinos undergoing endoscopy for gastroesophageal reflux disease symptoms, the prevalence of Barretts esophagus was 10%, comparable with non-Latino white controls as well as the prevalence previously reported among Caucasians. In addition to established risk factors, diabetes was associated with Barretts esophagus.

Management of inflammatory bowel disease: past, present and future.

The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, progressive inflamma tory disorders of the GI tract. The pathogenesis of IBD involves environmental, genetic and immuno logical factors. The past decade has seen a great change in the medical management of IBD, largely owing to the progress in basic research that continues to unravel its pathogenesis. The current review will focus on the milestones in IBD management that have occurred in the past decade (present), in the preceding 30–40 years (past) and the next decade (future). Past Evidence for the pathogenesis of IBD

Mo1688 Interobserver and Intraobserver Agreement of the Mayo Score of Endoscopic Activity in Ulcerative Colitis

After ileocecal resection, there is a high risk of recurrence on the ileocolic anastomosis and / or in the neoterminal ileum. The severity of endoscopic recurrence in the first year, assessed by the Rutgeerts score, can predict the risk of clinical recurrence and surgery. Treatments can be started immediately after surgery or in the presence of moderate or severe endoscopic lesions. Recent studies show that anti-TNF antibodies are very effective in preventing recurrence. However, there are only few data on the efficacy of anti-TNF antibodies initiated for a severe endoscopic recurrence. The main objective of this study was to evaluate the efficacy of anti-TNF on mucosal healing in patients with severe endoscopic recurrence (i3-i4). Methods: It is a retrospective, multicenter study from the GETAID. All GETAID centers were contacted to identify eligible cases (patients treated with anti-TNF for postoperative endoscopic recurrence). Inclusion criteria were: diagnosis of CD ileocecal resection with no residual macroscopic lesions Rutgeerts score (i3-i4) at ileocolonoscopy performed after surgery treatment with infliximab or adalimumab assessment of mucosal healing (Rutgeerts score). Results: Twenty-eight patients were included, 14 (50%) treated with adalimumab and 14 (50%) with infliximab. Partial mucosal healing (score i0 or i1) was achieved in 14 patients (50%). Complete mucosal healing (score i0) was obtained in 8 patients (29%) and improvement of endoscopic score (decrease of at least 1 point) was observed in 16 patients (57%). Fifty % of patients in the adalimumab group had received anti-TNF therapy before surgery versus 21% in the infliximab group (p=0.11). In multivariate analysis, there was a significantly better response on the partial mucosal healing in the group of patients treated with infliximab (p=0.03). Conclusion: Anti-TNFmonoclonal antibodies initiated after surgery because of a severe endoscopic recurrence (i3, i4) induce a partial mucosal healing in 50% of patients.

Does Endoscopic Assessment of Mucosal Healing Affect IBD Management

Diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD) relies on the combination of clinical, laboratory, and endoscopic data, which are needed for diagnosis according to adult and pediatric guidelines. Although the importance of an initial endoscopy is well documented, much less is known about the timing of and indications for follow-up endoscopy, with little stated in adult and pediatric guidelines and in the medical literature. Guidelines from the American Society for Gastrointestinal Endoscopy (ASGE) published in 2008 questioned the utility of endoscopy in exacerbations of pediatric IBD responding to therapy, citing poorer quality of life and perceived excess risk in the pediatric population [1]. Nevertheless, these questions had little supporting evidence until 2009, when a cross-sectional cohort study based at Baylor University was published, in which 285 endoscopic procedures in 230 children with established IBD performed for gastrointestinal bleeding, abdominal pain, weight loss, and diarrhea were evaluated. The authors reported that 42 % of procedures led to documented management changes such as a change of medication regimen, hospital admission, and surgical consultation [2]. Patients with CD (as compared to UC) and patients with mucosal injury (as compared to mucosal healing) were more likely to experience a management change with the initiation of medical therapy; of note, patient symptoms and laboratory values were not associated with a change in management. The authors concluded that endoscopic mucosal evaluation provided important independent data for the evaluation and management of pediatric IBD, particularly in CD. In the adult population, the value of repeated endoscopy is even less well studied. An early randomized clinical trial published by the GETAID group provided no data to support the value of colonoscopy in deciding the length of steroid treatment in colonic CD [3]. Of 136 patients in clinical remission for persistent disease, 96 with mucosal lesions were randomized to start a taper or continue prednisone at the same dose for 5 weeks before tapering. While the prolongation of prednisolone therapy improved endoscopic scores in that subgroup, the success of steroid weaning was almost identical between groups. Yet, in a parallel French study of 85 patients who underwent colonoscopy, 46 had severe and 39 had moderate endoscopic colitis, with response to medical therapy mostly observed in the latter group. [4]. In 2006, the ASGE reiterated an important finding from the literature: Subjective symptoms are not reliable indicators of disease severity, whereas endoscopy is an objective tool [5]. The technical review underlying the guidelines suggested that endoscopy may be helpful in predicting the need for intensified medical therapy or for surgical intervention. Nonetheless, no guidance is provided in the summary guidelines from the organization. The European Crohn’s and Colitis Organisation (ECCO) guidelines support the need for repeat endoscopy if the diagnosis remains in doubt, but do not support routine endoscopy for patients in clinical remission unless it is likely to change management [6]. ECCO guides that endoscopic assessment is indicated in cases of relapse, refractoriness, new symptoms, or when surgery is being considered. Nevertheless, no investigator has attempted to determine whether the findings reported in the 2009 pediatric study are applicable in adults until recently. In this issue of Digestive Diseases & Sciences, Kim et al. [7] attempted to replicate the Baylor pediatric study in an K. Keyashian (&) Oregon Health & Science University, Portland, OR, USA e-mail: keyashia@ohsu.edu

Novel Topics in Inflammatory Bowel Disease

We are pleased to announce the publication of the special issue focusing on novel topics in inflammatory bowel disease. It gained the interest of researchers from all over the world and more than 20 articles were submitted for review. Among them, our editorial team consisting of four renowned researchers in this field has selected six articles for publication. This includes basic and clinical research studies as well as translational research focusing on mechanism, epidemiology, treatment outcomes, and genetics. We are confident that this special issue advances the understanding and research of inflammatory bowel disease.