Irene Sonu

Clinical pharmacology of 5-ASA compounds in inflammatory bowel disease.

Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5-aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis.

Papillary thyroid cancer and inflammatory bowel disease: Is there a relationship?

AIM To formally study age of diagnosis of papillary thyroid cancer (PTC) in inflammatory bowel disease (IBD) patients and evaluate the prevalence of PTC in IBD patients compared to a control population. METHODS We were interested in testing the hypothesis that patients with IBD are more likely to be diagnosed with PTC than a control population. A retrospective cohort analysis was performed using the University of Pennsylvania Health Systems electronic database. Outpatients from 1998-2009 were included in the search, and patients in the cohort were selected based on ICD-9 codes. Inclusion criteria included the diagnosis of Crohns disease (CD) or ulcerative colitis (UC) and the concurrent diagnosis of thyroid cancer in comparison to a control population. Using these methods 912 patients with CD and 1774 with UC were compared to 1638 diverticulitis and 19 447 asthma controls. Statistics were performed using corrected chi-square analysis. The primary outcome for this study was the diagnosis of PTC. Approval to conduct this study was obtained by the Institutional Review Board at the University of Pennsylvania. RESULTS The mean age was 47.5 years (range: 18-102 years) and 66% patients were female. An analysis of variance model was used to compare the age of PTC diagnosis between the CD, UC, asthma and diverticulitis groups, and a statistically significant difference in age at PTC diagnosis was noted across all groups (F = 6.35, df = 3, P = 0.0006). The age of PTC diagnosis in CD patients was statistically significantly lower than UC, asthma, and diverticulitis patients (average PTC diagnosis age for CD 25, UC 49, asthma 45, diverticulitis 63). After covarying for sex and age in 2009, the difference in age at PTC diagnosis remained statistically significant (F = 4.13, df = 3, P = 0.0089). A total of 86 patients were diagnosed with PTC. Nine patients (0.5%) with UC were diagnosed with PTC. Patients with UC were not shown to be more likely to develop PTC [odds ratio (OR): 1.544, 95%CI 0.767-3.108] compared to asthma controls. Four patients (0.4%) with CD were diagnosed with PTC. Patients with CD were not shown to be more likely to develop PTC (OR: 1.334, 95%CI 0.485-3.672) compared to a control population with asthma. Nine patients (0.5%) with a history of diverticulitis were diagnosed with PTC. Patients with diverticulitis were not shown to be more likely to develop PTC (OR: 1.673, 95%CI 0.831-3.368) compared to asthma controls. Patients with CD or UC were not less likely to develop PTC compared to those with diverticulitis (CD OR: 0.80, 95%CI 0.25-2.60; UC OR: 0.92, 95%CI 0.37-2.33). None of the patients used immunosuppressant medications prior to the diagnosis of PTC (azathioprine, 6-mercaptopurine, and methotrexate). CONCLUSION There is a significant difference in age of diagnosis of PTC in patients with CD compared to patients with UC and the control populations studied.

5-ASA Induced Recurrent Myopericarditis and Cardiac Tamponade in a Patient with Ulcerative Colitis

A 20-year-old woman with recently diagnosed moderate left-sided ulcerative colitis (UC) presented to the emergency department (ED) for chest pain. Two months earlier, she had been evaluated in gastroenterology clinic for bloody diarrhea and crampy left lower quadrant abdominal pain. Stool tests for infectious causes were negative. Colonoscopy demonstrated diffuse mucosal erythema, linear ulcerations, and friability that extended continuously from the rectum to the descending colon (Fig. 1), histologically reported as acute and chronic colitis with crypt architectural distortion, consistent with inflammatory bowel disease. No granulomas or viral inclusion bodies were seen. Institution of sulfasalazine 500 mg four times daily and mesalamine enemas significantly improved her symptoms. Three weeks later, she presented to the ED with pleuritic chest pain, aggravated by lying flat and relieved by leaning forward. She denied nausea, vomiting, coryza, or cough. She was afebrile, with a heart rate 116 beats per minute and blood pressure 102/67 mmHg. Physical exam was notable for a friction rub heard loudest over the left sternal border, mild epigastric tenderness, and 1? pitting edema to the mid-shin. Laboratory examination revealed leukocytosis with neutrophilia (WBC 16.8 k/ll, 82.8 % neutrophils), elevated troponin, creatine kinase-myocardial band (CK-MB), erythrocyte sedimentation rate (ESR), and C-reactive protein. ECG revealed diffuse ST elevation. Echocardiography revealed a small pericardial effusion with normal systolic function (Fig. 2), which was also noted in the CT angiogram report, with no evidence of pulmonary embolism or other chest pathology. The patient was diagnosed with acute myopericarditis. Direct fluorescent antibody test for respiratory viruses, blood cultures, HIV antibody screen, PPD, and autoantibodies (including anti-nuclear antibody, anti-double-stranded DNA, and others) were all negative. Although viral myopericarditis could not definitively be excluded (since not all implicated viruses can be tested for), the main concern was for a reaction to sulfasalazine or, less likely, rectal mesalamine. Sulfasalazine was thus discontinued, mesalamine enemas were switched to hydrocortisone enemas, and she was treated with ibuprofen and colchicine, with symptom resolution. Low-dose balsalazide was then cautiously initiated. Five days later, the patient returned with recurrent severe pleuritic chest pain. She was hypotensive (85/52 mmHg) and tachycardic (117 bpm). Her ECG showed diffuse T wave flattening without electrical alternans. Bedside echocardiogram revealed a large pericardial effusion with hemodynamic compromise consistent with cardiac tamponade (Fig. 2). She underwent emergent pericardiocentesis with drainage of 300 ml of serosanguinous fluid. Fluid analysis and cultures were unrevealing. She was again treated with ibuprofen and colchicine, with discontinuation of the balsalazide, accompanied by marked improvement of her chest pain. Hydrocortisone enemas were prescribed with a plan for immunomodulator I. Sonu R. Wong M. E. Rothenberg Department of Medicine, Stanford University Medical Center, Stanford, CA, USA

Persistent constipation and abdominal adverse events with newer treatments for constipation

Background Clinical trials of several new treatments for opioid-induced constipation (OIC), chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) have focused on differences between subjects relieved of constipation with placebo and active treatment. Patients and clinicians however, are more interested in the probability these treatments provide actual relief of constipation and its associated symptoms. Methods We searched the medical literature using MEDLINE and Cochrane central register of controlled trials. Randomised, placebo-controlled trials that examined the use of methylnaltrexone, naloxegol, lubiprostone, prucalopride or linaclotide in adults with OIC, CIC and IBS-C were eligible for inclusion. The primary efficacy measure was relief of constipation. Adverse event data for abdominal symptoms were also analysed. Key results and findings 25 publications were included in our analyses. The proportion of constipated individuals with active treatment was significantly lower than the proportion with placebo; however, in 15 of these 20 trials analysed, a majority of patients remained constipated with active treatment. Analyses of adverse event data revealed that the percentage of participants who experienced abdominal pain, diarrhoea and flatulence with active treatment was higher than that with placebo in the majority of trials analysed. Conclusions Newer pharmacological treatments for constipation are superior to placebo in relieving constipation, but many patients receiving active treatment may remain constipated. In addition, all 5 of the treatments studied are accompanied by no change or a possible increase in the prevalence of abdominal symptoms, such as abdominal pain, diarrhoea and flatulence.

Use of Esophageal pH Monitoring to Minimize Proton-Pump Inhibitor Utilization in Patients with Gastroesophageal Reflux Symptoms

BackgroundDue to concerns about long-term PPI use in patients with acid reflux, we aimed at minimizing PPI use, either by avoiding initiating therapy, downscaling to other therapies, or introducing endoscopic or surgical options.AimsTo examine the role of esophageal ambulatory pHmetry in minimizing PPI use in patients with heartburn and acid regurgitation.MethodsRetrospective cohort analysis of patients with reflux symptoms, who underwent endoscopy, manometry, and ambulatory pHmetry to define the need for PPI. Patients were classified as: (1) never users; (2) partial responders to PPI; (3) users with complete response to PPI. Patients were then managed as: (1) PPI non-users; (2) PPI-initiated, and (3) PPI-continued.ResultsOf 286 patients with heartburn and regurgitation, 103 (36%) were found to have normal and 183 (64%) abnormal esophageal acid exposure (AET). In the normal AET group, 44/103 had not been treated and were not initiated on PPI. Of the 59 who had previously received PPI, 52 stopped and 7 continued PPI. Hence, PPI were avoided in 96/103 patients (93%). In the abnormal AET group, 61/183 had not been treated and 38 were initiated on PPI and 23 on other therapies. In the 122 patients previously treated with PPI, 24 were not treated with PPI, but with H2RAs, prokinetics, endoscopic, or surgical therapy. Hence, PPI therapy was avoided in 47/183 patients (26%).ConclusionsIn patients with GER symptoms, esophageal pHmetry may avert PPI use in 50%. In the era of caution regarding PPIs, early testing may provide assurance and justification.

1018 A Questionable Investment for Our Patients: Challenging the Efficacy of New Therapies for Opioid-Induced and Chronic Idiopathic Constipation

Introduction. Opioid-induced and chronic idiopathic constipation are common disorders that remain great treatment challenges. Clinical trials of several new, expensive treatments for these conditions have focused on differences between subjects relieved of constipation with placebo and active treatment. Patients and clinicians, however, are more interested in the probability these treatments provide actual relief of constipation and its associated symptoms. Methods. We analyzed published data from randomized, placebo-controlled clinical trials of five different treatments for opioid-induced and chronic idiopathic constipation. Active treatments were: Methylnaltrexone (NEJM 358:2332, 2008), Naloxegol (NEJM 370:2387, 2014), Lubiprostone (Am J Gastro 103:170, 2008), Prucalopride (NEJM 358:2344, 2008), and Linaclotide (NEJM 365:527, 2011). We used beta distributions to calculate probability intervals. Results. Across all five studies, the proportion of constipated subjects with active treatment was significantly lower than the proportion with placebo; however, a substantial proportion of patients remained constipated with active treatment (Methylnaltrexone 52%, Naloxegol low-/high-dose 62%/58%, Lubiprostone 42%, Prucalopride low-/highdose 69%/72%, Linaclotide low-/high-dose 81%/80%). Figure 1 displays the proportion of patients who remained constipated with active treatment and placebo. The 95% probability for remaining constipated with active treatment ranged from at least 34% with Lubiprostone to at least 78% with Linaclotide. The proportion of patients experiencing abdominal pain during the study was greater for patients on active treatment compared to placebo across all five studies (Methylnaltrexone vs placebo 18% vs 13%, Naloxegol lowvs high-dose vs placebo 10% vs 16% vs 6%, Lubiprostone vs placebo 5% vs 1%, Prucalopride lowvs highdose vs placebo 19% vs 22% vs 19%, Linaclotide lowvs high-dose vs placebo 4% vs 5% vs 3%). Similar results were seen for diarrhea during the study (Methylnaltrexone vs placebo 6% vs 4%, Naloxegol lowvs high-dose vs placebo 6% vs 9% vs 4%, Lubiprostone vs placebo 5% vs 2%, Prucalopride lowvs high-dose vs placebo 14% vs 19% vs 5%, Linaclotide lowvs high-dose vs placebo 16% vs 14% vs 5%), and flatulence during the study (Methylnaltrexone vs placebo 13% vs 7%, Naloxegol lowvs high-dose vs placebo 3% vs 6% vs 2%, Lubiprostone vs placebo 6% vs 1%, Prucalopride lowvs high-dose vs placebo 11% vs 8% vs 9%, Linaclotide lowvs high-dose vs placebo 6% vs 5% vs 5%). Conclusion. Currently available treatments for opioid-induced or chronic idiopathic constipation are ineffective in a substantial portion of patients. These treatments also fail to relieve accompanying adverse symptoms, and may actually exacerbate them.

T1287 Risk of Postoperative Infections in IBD Patients Treated With Perioperative Anti-TNF Therapy: A Meta-Analysis

Results: In our study cohort (mean age 60.2 ±11.8 years, 57.5 % females, 17 % current smokers, median follow up 292 days), 135 patients underwent 340 endoscopic stricture dilations (159 primary and 181 anastomotic). The median intervention-free (repeat dilation or surgery) period was 140 days and there were total of 4 complications (3 perforations, 1 major bleeding). There was no difference between primary or anastomotic strictures with respect to need for surgery (p=0.17, Figure), intervention-free period (p= 0.24) or perforation rate (0.7% versus 1.2%, p= 0.57). 36 patients (26.7%) underwent surgery in the follow-up period. Multivariate Cox regression analysis showed that inflamed mucosa (hazard ratio [HR] 2.3, p=0.04) and colonic location (HR, 2.5, p=0.03) were significantly associated with increased risk for future surgery while intramucosal steroid injection did not confer any benfit. Conclusion: In this largest experience reported so far, we have found that endoscopic dilation is very safe and effective for CD patients with anastomotic as well as non-anastomotic strictures. Future studies should aim to investigate endoscopic and pharmacologic interventions that can prolong the intervention-free period and improve longterm outcomes.

W1201 The Risk of Infectious Complications Associated With the use of Immunosuppressive Medications in Elderly Patients With Inflammatory Bowel Disease

Background: The use of immunsuppressive agents (ISA) is associated with (a/w) significant adverse events,including infectious complications (IC) in IBD pts. In the TREAT registry (CGH 2006;4:621-630) age and prednisone use in IBD pts were a/w increased mortality and IC. The use of infliximab was suggested to be a/w an increased mortality rate in elderly pts treated for IBD (Gastroenterology 2004;126:19-31). 6-MP/azathioprine was well tolerated by the elderly in an uncontrolled trial (AJG 2009;14:1171). No studies were published comparing IC a/w the different immunosuppressive medications between elderly and young. Aim: To assess if age is an independent risk factor for prediction of IC in IBD pts exposed to ISA. Methods: We searched our electronic medical records to identify pts with CD/UC aged >17 between 2007-2009. Pts with cancer, immunodeficiency and exposure to ISA for other reasons were excluded. Data on demographics, IBD subtypes, co-morbidities, medication details and infections were collected and analyzed. Results: 48 pts with IBD and age >65 yrs and 162 pts with IBD and age 17 yrs were identified. The demographics, IBD subtypes, co-morbidities (e.g. DM, CHF, CAD, CKD/CRF, cirrhosis, obesity and depression) and IC are in Table 1. The ISA exposures for both groups are in Table 2. Elderly pts were 5 times more likely to have IC compared to young pts (OR=5.07, 95% CI 1.87-13.70, p=0.0014). Pts with co-morbidities were 8 times more likely to develop infections (OR= 8.60, 95% CI 3.06-24.18, p<0.0001)than pts without co-morbidities. 5% of young pts, 10% of elderly without co-morbidities, and 30% of elderly with co-morbidities had IC (p=0.0006). In the multivariable logistic regression model for risk of IC, age and co-morbidity were the only predictors a/w significant increase of IC. Sex, race, IBD subtype, CS/IMM/Bio exposure were not significantly a/w IC when comparing the two groups. Conclusion: There is an increased risk of IC in the elderly. Age and co-existing co-morbidities are independent risk factors for prediction of IC in IBD pts exposed to ISA. Table 1