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Highlights from the 15th Annual Gastroenterology/Hepatology Update Chair Douglas K. Rex, MD

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his CME newsletter, based on the 2012 Gastroenterology/Hepatology Update meeting, will provide expert perspectives from Indiana University School of Medicine’s distinguished faculty on new developments in gastroenterology and hepatology. These insights will help busy gastroenterologists, internists, family practice physicians, and other primary care providers evaluate results of recent breakthrough research for their implications for today’s clinical practice. Key features of the 2012 program include presentations on new and updated clinical information, as well as treatment and management updates for gastroenterologic and hepatologic diseases. A review of potentially practice-changing studies will be provided in a number of areas, such as upper and lower gastrointestinal tract diseases, liver disease, and pancreatobiliary disease. Finally, clinical recommendations will be offered to help improve practice and, ultimately, patient outcomes.

Update in Colorectal Cancer Screening Douglas K. Rex, MD, Distinguished Professor of Medicine and Chancellor’s Professor, presented an update on colorectal cancer screening, including a discussion about the criteria by which the quality of colonoscopy can be evaluated. Every colorectal cancer (CRC) is unique from a molecular standpoint and has its own unique genetic profile of mutations. However, gene mutations in 3 general pathways define the molecular basis of CRC: the chromosomal instability pathway (CIN; tumor suppressor and oncogene mutations), the Lynch pathway (mutations in mismatch repair genes), and the CpG island meth-

ylator phenotype (CIMP) pathway (hypermethylation of genes), which accounts for about 30% of colorectal cancers. The precursor for CIMPpositive tumors is not the traditional adenomatous polyp, but a different sort of polyp called a serrated lesion. The serrated lesions are classified as hyperplastic polyp (HP); sessile

serrated adenoma/polyp (SSA/P), which can be with cytological dysplasia or without cytological dysplasia; and traditional serrated adenoma (TSA). SSA/P is the main precursor of CIMPhigh CRC. Presently, there is no reli-

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able way to distinguish HP from SSA/P endoscopically.1 Most large serrated lesions in the proximal colon are SSA/P. In particular, SSA/P with cytological dysplasia is a dangerous lesion. The commonly used CRC screening tests in the United States are the guaiacbased fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and colonoscopy. Although not commonly

used, the most promising stool test may be the fecal DNA test, because hypermethylated genes can be easily detected in the stools. A large-scale randomized controlled trial of FIT

versus gFOBT in 20,623 participants showed better adherence and positivity rate for FIT (59.6% and 5.5%, respectively) compared with gFOBT (46.9% and 2.4%, respectively).2 Septin 9 is a new blood test not yet approved by the U.S. Food and Drug Administration (FDA) that tests for hypermethylation of the septin 9 gene. When compared with the fecal DNA test, the septin 9 test performed poorly in terms of specificity, as well as sensitivity, for stage I to stage III cancer and large adenomas.3 Computed tomographic (CT) colonography is another screening technique that is seldom used in CRC surveillance. It is not approved by the U.S. Preventive Services Task Force because of the radiation risk and likeli-

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Distinguished Professor of Medicine Chancellor’s Professor Indiana University-Purdue University Indianapolis Indianapolis, IN

Learning Objectives

This activity is designed for specialists in gastroenterology, internal medicine, family practice, and primary care. There are no prerequisites for this activity. At the conclusion of this activity, participants should be able to: • Identify and screen patients with average and high risk for colorectal cancer to prevent colorectal cancer and reduce cancer mortality based on the American College of Gastroenterology guidelines. • Examine patients for Barrett’s esophagus based on American College of Gastroenterology guidelines and conduct cost-effective surveillances. • Use management strategies for gastroesophageal reflux disease (GERD) recommended by the American College of Gastroenterology to improve quality of life in patients with GERD. • Evaluate and treat patients with abnormal liver test results and patients with viral hepatitis using American Association for the Study of Liver Diseases screening guidelines to prevent cirrhosis in patients. • Optimize outcomes of treatment for hepatitis C by considering the use of new protease inhibitors. • Employ current guidelines regarding screening in a consistent manner so as to identify and screen all patients at risk for hepatitis B infection. • Apply current guidelines to identify patients at high risk for hepatocellular carcinoma, screen using recommended modalities, and follow up with appropriate treatment or referral. • Describe the implications for clinical practice of recent advances in the management of lower gastrointestinal tract disease, GERD, and pancreatic and pelvic floor disorders.

CME Information

Release Date: August 15, 2012. Valid for credit through August 14, 2013. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Indiana University School of Medicine and Heath Focus, Inc. Indiana University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Indiana University School of Medicine designates this enduring activity for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To receive credit, participants must read this newsletter and submit the activity evaluation form and posttest (passing score = 75% or higher). Length of time to complete the activity: 2 hours

Disclosure Information Commercial Support

Indiana University School of Medicine and Health Focus, Inc. gratefully acknowledge the unrestricted educational grant provided by Vertex.

Faculty Disclosure In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, and planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity. Dr. Rex reported that he has received consulting fees and/or honoraria from American BioOptics, Braintree, Boston Scientific, CheckCap, Epigenomics, Exact Sciences, Given Imaging, and Olympus. Staff: Hassan Danesh, PhD, Monica Armin, and Dr. Deborah Teplow have disclosed that they have no potential or actual conflicts of interest. Note: Although it offers CME credits, this activity is not intended to provide extensive training or certification in the field.


hood of extracolonic findings. It is also not approved by Centers for Medicare & Medicaid Services because of insufficient data in the elderly and because it is less cost-effective than colonoscopy. Capsule colonoscopy, which requires extensive bowel preparation, is yet another non–FDA-approved screening method, with a sensitivity greater than 80% for polyps 6 mm and smaller and a specificity of less than 80%. The adenoma detection rate (ADR), the primary measure of the quality of colonoscopy, varies greatly among gastroenterologists; the lowest ADR ranges from 7% to 15.5% and the highest ADR ranges from 32.7% to 44%. Some of the factors that may underlie the variable detection rate are training (eg, lesion recognition, withdrawal technique, and withdrawal time), personality, visual gaze patterns, and withdrawal time. A prospective study demonstrated that adequate bowel preparation results in a detection rate of 29.4% for any adenoma and a detection rate of 6.4% for large adenomas (>1 cm) when compared with inadequate bowel preparation, which showed a detection rate of 23.9% for any adenoma and a detection rate of 4.3% for large adenomas (P < .05).4 In bowel preparation, split-dosing has been shown to provide more satisfactory results than traditional dosing.5 Thus, the components of good detection are a good bowel preparation, adequate time, and a sound technique.

Barrett’s Esophagus: Screening, Surveillance, Diagnosis, and Treatment Douglas K. Rex, MD, Distinguished Professor of Medicine and Chancellor’s Professor, presented current perspectives on screening, surveillance, diagnosis, and treatment of Barrett’s esophagus. Barrett’s esophagus (BE) is characterized by red (columnar) mucosa in the esophagus and described according to Prague’s classification based on the following criteria: (1) C: length of the circumferential section; and (2) M: length of any circumferential section, plus the length of any tongues. Biopsies will demonstrate goblet cells, which are not seen in the normal stomach, but are seen in the intestine.

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How Do We Achieve Excellence in Screening? „„ Use high-quality colonoscopists -- Should be able to quote ADR -- Should see split-dose preparations -- Should see consistent photographic documentation of cecal intubation -- Should see appropriate use of follow-up exams „„ Switch from gFOBT to FIT -- Avoid examining specimens from DRE These cells define the intestinal metaplasia. The risk of esophageal adenocarcinoma is associated with being a white male; the presence of BE, chronic gastrointestinal disease, or obesity; and a family history of esophageal carcinoma. In fact, 85%

of the cases of BE are in white males. The stages of BE are classified as simple

Barrett’s (no dysplasia), Barrett’s with low-grade dysplasia, Barrett’s with highgrade dysplasia (HGD), and adenocarcinoma. The American College of Gastroenterology has specific recommendations for the surveillance intervals for patients with BE.6 Three studies that assessed the

risk of cancer development in patients with HGD who were followed up for 8, 7, and 5 years, respectively, suggest that 6% to 8% of these patients develop cancer.7-9

Nodular disease in BE patients must be removed by endoscopic mucosal resection (EMR), which is an effective therapy for nodules with HGD or intramucosal carcinoma and provides more accurate staging than endoscopic ultrasonography. The best treatment for flat disease is radiofrequency ablation (RFA). Alternative therapies include cryotherapy, photodynamic therapy, and argon plasma coagulation or multipolar cautery.

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Esophagectomy is generally recognized to have greater morbidity and mortality than any elective operation performed in the United States. A study assessed 30-day mortality in patients admitted to hospitals that performed from fewer than 2 esophagectomies per year to approximately 2 to 6 esophagectomies per year.10 The 30-day mortality rate decreased as the number of surgeries performed per year increased, suggesting that the higher the volume of esophagectomies, the better the results. However, factors such as the patient’s age and the existence of comorbidities will increase the mortality rate from esophagectomy. EMR is not recommended for excising long segments of BE because it is associated with distortion of anatomy for subsequent radiofrequency ablation, stricture formation, bleeding, and perforation. EMR is an adequate therapy for BE if it fully removes the damaged lining. If there is residual Barrett’s tissue after EMR, then RFA should be used to complete ablation.

Hepatocellular Carcinoma: The Growing Disease Burden Paul Y. Kwo, MD, Professor of Medicine and Medical Director, Liver Transplantation, discussed key aspects of hepatocellular carcinoma, from epidemiology to treatment.


Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and is the third leading cause of cancer-related deaths. Although HCC is associated with hepatitis B worldwide, hepatitis C has driven the rapid rise in HCC (50%-70% of all HCC cases) in the United States, where the ageadjusted incidence of HCC has doubled from 1985 to 1998. Other risk factors in the United States include alcohol use, nonalcoholic fatty liver disease, inherited liver disease, smoking, and

hemochromatosis.

Two key mechanisms are implicated in the development of HCC: liver cirrhosis following tissue damage (infectious or toxic damage) and mutations occurring in 1 or more oncogenes or tumor suppressor genes. The mean doubling time for the majority of HCC tumors is 4 months,11 and these tumors are

biologically aggressive. The prognosis of symptomatic patients is very poor, particularly because 90% of these individuals have underlying cirrhosis. Following intrahepatic metastases and vascular invasion, HCC can spread to the lungs, bones, and adrenal glands.

The first step in HCC screening is to identify the individuals at risk; that is, to identify individuals with liver cirrhosis. Ultrasonography every 6 months to 12 months with assessment of alpha-fetoprotein every 6 months is the current standard of care for screening high-risk patients (hepatitis B carriers and patients with nonâ&#x20AC;&#x201C;hepatitis-B cirrhosis), similar to guidelines of the American Association for the Study of Liver Diseases. Alphafetoprotein assessment alone is not sufficient, unless imaging modalities are not available. The common practice at Indiana University is to perform magnetic resonance imaging (MRI) every 9 months, or dual-phase helical CT or ultrasound every 6 months to 12 months if the body mass index is normal. HCC is diagnosed by dual-phase helical CT scan or MRI with intravenous contrast. A retrospective analysis of 269 patients with cirrhosis and HCC showed HCC was diagnosed at stages 1 and 2 in 70% of patients in the group with standardof-care surveillance, 37% of patients with substandard surveillance, and only 18% of

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Prognosis of Patients With HCC: Patient Survival Therapy

1 Year

3 Years

No radical therapy

54%

28%

Surgical resection

81%

44%

Ethanol injection

82%

38%

Transplatation

84%

74%

Castells A, et al. Hepatology. 1993;18:11211. Llovet JM, et al. Hepatology. 1998;27:1572. Llovet JM, et al. Hepatology. 1999;29:62

patients with no surveillance. Moreover, the ability to provide liver transplantation and the 3-year survival rate following diagnosis increased when the standardof-care surveillance is followed.12 The current treatment options for HCC include surgical resection, liver transplantation, transarterial chemoembolization or radioembolization (yttrium-90 [Y90] microspheres), stereotactic radiation, radiofrequency ablation, and sorafenib. The 5-year survival rate for surgical resection is 60% to 70%, and the tumor recurrence rate is 50% in 3 years.13 Liver transplantation offers the best chance for cure in selected cases.14,15 Living donor transplantation may provide timely transplantation. Radical (stereotactic radiation and radiofrequency ablation therapies are effective for small tumors before orthotopic liver transplantation (OLT). Radioembolization (Y90) in nontransplant patients appears to improve survival. Sorafenib conferred a survival benefit in unresectable HCC16 and is being studied in multiple patient populations with HCC.

Breakthrough Papers on Lower Gastrointestinal Tract in 2011 Charles J. Kahi, MD, MSc, Associate Professor of Clinical Medicine and Chief, Gastrointestinal Section, Roudebush VA Medical Center, Indianapolis, reviewed

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several key papers from 2011 on lower gastrointestinal tract disease. Rifaximin therapy for patients with irritable bowel syndrome without constipation.17 Patients with irritable bowel syndrome (IBS) may have altered intestinal microbiota, and systemic antibiotics have been used with mixed results. Rifaximin is a minimally absorbed, broad-spectrum antibiotic that has shown efficacy for IBS in small-scale studies. Two multicenter, industry-supported, randomized controlled trials (TARGET 1 and TARGET 2) involved 1260 patients with IBS (Rome II criteria) without constipation, who were randomized in a 1:1 ratio to rifaximin (550 mg by mouth 3 times daily) or placebo for 2 weeks. The primary end point was the proportion of patients who reported adequate relief of IBS symptoms for at least 2 weeks of the first 4 weeks after treatment completion. The secondary end point was relief of IBS-related bloating. The primary and secondary end points were reached in 40.7% and 40.2% of patients, respectively, in the rifaximin arm compared with 31.7% and 30.3% in the placebo arm (P < .001). The results indicated a durable response to rifaximin over 3 months and a safety profile of rifaximin that is similar to placebo. However, a very high response rate was seen in the placebo arm.


Fidaxomicin versus vancomycin for Clostridium difficile infection.18 Increasing disease severity and recurrence rates have been observed in Clostridium difficile infection (CDI), which is usually treated with metronidazole or vancomycin. Fidaxomicin is a new macrocyclic antibiotic with no crossresistance with other antibiotics. The present study was a noninferiority multicenter phase III randomized controlled trial of 629 adults randomized in a 1:1 ratio to fidaxomicin (200 mg twice daily) or to vancomycin (125 mg 4 times daily) for 10 days. The primary end point at 4-week follow-up was clinical cure, defined as resolution of diarrhea and no need for additional CDI therapy. The secondary end point was CDI recurrence within 4 weeks after therapy. Clinical cure rates with fidaxomicin were noninferior to clinical cures rates with vancomycin (88.2% vs 85.8%). The results showed that recurrence rates were significantly lower in the fidaxomicin group (15.4% vs 25.3%; P = .005). Lower recurrence rates were seen in patients with non-nucleosome assembly protein-1 strains (69% relative reduction). Fidaxomicin can be potentially advantageous in the treatment of CDI because a reduction in recurrence also likely decreases person-to-person transmission (â&#x20AC;&#x153;global cureâ&#x20AC;?). Moreover, fidaxomicin is bactericidal specifically against C. difficile, but preserves normal anaerobic flora (less recurrence, possibly less vancomycin-resistant enterococci). However, its use may be precluded by the expense: $2800 for a 10-day course. Use of aspirin or nonsteroidal antiinflammatory drugs increases risk for diverticulitis and diverticular bleeding.19 Case-control studies have suggested a higher prevalence of nonsteroidal anti-inflammatory drug (NSAID) use in patients with complicated diverticular disease (bleeding, diverticulitis). This was a prospective study of a large cohort of men (N = 47,210; aged 40-75 years) enrolled in the Health Professionals Follow-up Study. Methods included supplementary questionnaires and assessment of aspirin and nonaspirin NSAID use and diverticulitis or diverticular bleeding. Bleeding risks for aspirin and NSAIDS were similar (hazard ratio = 1.7).

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Regular use of aspirin and NSAIDs was associated with an increased risk of diverticulitis and diverticular bleeding. These results have important clinical and public health implications given the prevalence of diverticulosis and NSAID use in the elderly. Aspirin and NSAIDs should be used with caution in patients at risk of diverticular complications.

Breakthrough Papers in Hepatology in 2011 Marco A. Lacerda, MD, Associate Professor of Clinical Medicine, reviewed several papers from 2011 in hepatology with implications for clinical practice. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary Patients sclerosing cholangitis.20 with ulcerative colitis and primary sclerosing cholangitis (UC/PSC) are at higher risk for colorectal neoplasia. In this study, patients with UC/PSC who were previously enrolled in a trial of high-dose ursodeoxycholic acid (UDCA) were analyzed for the development of colorectal neoplasia. Of the 56 patients enrolled in the previous study, 25 were in a UDCA group and 31 were in a placebo group. Surveillance colonoscopy and pathology (mean time = 4.4 years) indicated that 9 of the 25 (36%) UDCA-treated patients developed neoplasia (1 cancer, 1 highgrade, 7 low-grade). Three of the 31 (9.7%) patients in the placebo group developed neoplasia (1 cancer, 1 highgrade, 1 low-grade; hazard ratio = 4.4; P = .02). This study demonstrated that long-term use of high-dose UDCA in patients with UC/PSC is associated with increased risk of colorectal neoplasia. Early liver transplantation for severe This study alcoholic hepatitis.21 analyzed the effect of early liver transplant (patients with < 6-month sobriety) on 6-month survival of 26 patients with severe alcoholic hepatitis. The patients had no prior episodes of alcoholic hepatitis and had scores of 0.45 or higher according to the Lille model (which calculates scores ranging from 0 to 1, with a score of at least 0.45 indicating nonresponse to medical therapy and an

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increased risk of death in the absence of transplantation) or rapid worsening of liver function despite medical therapy. The results demonstrated that the 6-month survival of those who underwent early liver transplant was higher than that of 26 matched nonrandomized control patients (77% vs 23%; P < .001). However, 3 patients resumed drinking posttransplantation. The study showed that early liver transplantation can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. Rifaximin treatment in hepatic encephalopathy.22 A total of 299 patients who were in remission from recurrent hepatic encephalopathy (HE) resulting from chronic liver disease received either rifaximin at a dosage of 550 mg twice daily (140 patients) or placebo (159 patients) for 6 months. The primary end point was the time to the first breakthrough of HE, and the secondary end point was the time to the first hospital admission due to HE. Rifaximin was superior to placebo in maintaining remission from HE and significantly reducing hospitalizations due to HE-related episodes. No obvious cognitive deficits or impaired quality of life were observed after rifaximin treatment. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial.23 Nonalcoholic fatty acid liver disease (NAFLD) is defined as a spectrum from benign steatosis to necroinflammatory changes and fibrosis. In this study, 1005 patients were randomized to receive atorvastatin (20 mg), vitamin C (1 g), and vitamin E (1000 IU) or matching placebo as part of the St Francis Heart Study randomized clinical trial. Follow-up was an average of 3.6 years. CT scans of the patients were used to calculate liver to spleen ratios in 455 patients at baseline and at follow-up. The study demonstrated that after 4 years of therapy, atorvastatin plus vitamins C and E lowered the risk of moderate-tosevere hepatic steatosis by 70% in the 80 patients who had NAFLD at baseline. Baseline triglyceride levels (odds ratio [OR] = 1.003; P < .001) and body mass index (OR = 0.10; P < .001) were independent predictors of NAFLD.


Breakthrough Papers in Upper Gastrointestinal Tract in 2011 Lee McHenry, MD, Professor of Medicine and Medical Director, IU Spring Mill Medical Clinics, Carmel, Indiana, examined breakthrough papers in upper gastrointestinal tract from 2011, including papers on Helicobacter pylori, celiac disease, and gastroesophageal reflux disease. Randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple therapy for the eradication of Helicobacter pylori.24 H. pylori is a Class I carcinogen. The current standard of care (proton pump inhibitors plus amoxicillin and cla-rithromycin) fails in 30% of patients, mainly because of drug resistance to clarithromycin. This study was a randomized, prospective, open-labeled trial of LOAD-7 (levofloxacin once daily; omeprazole once daily; nitazoxanide [antiprotozoal agent] twice daily, and doxycycline once daily for 7 days) or LOAD-10 (the same regimen for 10 days); the combined efficacy of the LOAD therapies was compared with LAC therapy (lansoprazole, amoxicillin, and clarithromycin). The eradication rates of LOAD-7 and LOAD-10 were 88.9% and 90%, respectively, and the combined LOAD efficacy was 89.4%, which was significantly higher than that of LAC therapy (73.3%). These results are particularly robust considering that these efficacies were determined in the intention-to-treat population. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease.25 The gold standard to diagnose celiac disease is biopsy of the more distal duodenum showing villous atrophy (VA). In this study, the biopsy findings of the duodenal bulb and distal duodenum of patients with newly diagnosed and established celiac disease were compared with those of control patients. The diagnosis was considered positive only when the Marsh stage 3 criteria were met (epithelial lymphocytes, hyperplasia, and partial VA). Interestingly, patients with newly diagnosed celiac disease (9%) and with established celiac disease (14%) were more likely to have VA in the duodenal bulb alone than were control patients. Hence, this study is important because it would enable the diagnosis of an additional

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10% to 15% of patients by performing a duodenal bulb biopsy in addition to distal duodenal biopsies. Therefore, duodenal bulb biopsy should be performed in addition to distal duodenal biopsy in patients with suspected celiac disease. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial.26 This was a randomized multicenter parallel-group study of 554 patients with chronic gastroesophageal reflux disease (GERD). The remission rates of the laparoscopic 360-degree Nissen fundoplication with posterior crural repair were compared with esomeprazole (20-40 mg/d). At the 5-year follow-up, the remission rate (the need for more than 40 mg of esomeprazole) was 93% in the medical arm and 85% in the surgical arm. The 5-year remission rates in this study are higher than those in previous studies. It appears from these results that we are losing some of the durability of the surgical repair. However, considering the long-term side effects of proton pump inhibitors, such as osteoporosis and pneumonia, antireflux surgery may be an acceptable option in the future. Pregnancy outcome and risk of celiac disease in offspring: a nationwide casecontrol study.27 This was a populationbased case-control study that evaluated the risk of celiac disease in newborns who were exposed to cesarean delivery (elective or emergency) and adverse fetal events (low Apgar score, small for gestational age, low birth weight, and preterm). A comparison of 11,000 offspring with biopsy-verified celiac disease with 53,000 age- and sex-matched control patients found a positive association between celiac disease and elective cesarean delivery. Newborns who were small for gestational age had a 21% increased risk of celiac disease; whereas, other pregnancy exposures did not increase the risk of future celiac disease. The emergency cesarean did not increase the risk, thus the bacterial flora of the newborn may play a role in the development of celiac disease.

Intestinal Transplantation: Definition, Advantages, and Risks Richard Mangus, MD, Assistant Professor of Surgery, described the advantages and risks

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of intestinal transplantation and illustrated its cost benefit as compared with parenteral nutrition. Intestinal failure is defined as the inability of the intestinal tract to maintain adequate nutritional status and fluid/electrolyte balance. It results from a loss or absence of sufficient functional intestinal area. Management approaches include medical or surgical alteration of the damaged area, parenteral nutrition, and intestinal transplantation. Intestinal transplantation has many advantages over other treatment options: it replaces normal intestinal anatomy and continuity; the patient is able to eat and drink; it provides a chance for definitive cure of disease; parenteral nutrition can be stopped, which decreases infection risk; and it leads to a reversal of liver injury. However, it is also associated with the risks of major surgery, host rejection, and life-long immunosuppression. An isolated intestinal transplant is indicated when there is intestinal failure in the absence of any other organ failure and when the normal function of liver, stomach, and pancreas are intact. A modified multivisceral transplant is performed when there is intestinal failure in the absence of liver failure and the liver function is normal, but there is dysfunction of the stomach and intestine, with or without pancreatic dysfunction. A multivisceral transplant is usually indicated in intestinal failure accompanied by liver failure, with or without the dysfunction of stomach and pancreas. Intestinal transplantation is also considered for certain nontraditional indications, such as diffuse mesenteric thrombosis, benign/low-grade malignant tumors involving the mesenteric root, neuroendocrine tumors (carcinoid, insulinoma, others), desmoid tumors, abdominal catastrophes/fistulas, radiation enteritis, trauma, and enteropathies/ dysmotility disorders. For isolated and modified multivisceral transplants (liver excluded), the 1-year risk of rejection is 45% to 50%. For multivisceral transplants (liver included), the 1-year risk of rejection is 15%. The liver is known to be protective against rejection. Additional complications include graft versus host disease; posttransplant lymphoproliferative


disorder; disease recurrence; and pseudo-obstruction that encompasses obstruction, chronic rejection, and narcotic addiction (chronic pain). Between 2005 and 2007, 28 centers worldwide reported to the worldwide database of all intestinal transplants that 389 intestinal transplants were performed on 377 patients. In the United States, 151 transplants were reported in 2010 (16% fewer than in 2009). There were 17 centers with at least 1 transplant and 6 centers with 10 or more intestinal transplants. Intestinal transplantation has been shown to be a cost-effective therapy and is superior to continued parenteral nutrition in appropriately selected patients. Costs for intestinal transplantation, including the initial hospitalization for the transplant, range from $200,000 to $500,000. There are frequent hospital readmissions posttransplant, but these admissions decrease markedly after the second year. The cost benefit of transplantation reaches parity with parenteral nutrition after 2 years to 3 years posttransplant and is more cost-effective thereafter.

Viral Hepatitis Update Paul Y. Kwo, MD, Professor of Medicine and Medical Director, Liver Transplantation, described new developments in the treatment of hepatitis B and hepatitis C, and gave practical clinical tips. Hepatitis B In the Unites States, there are approximately 2 million people infected with hepatitis B virus (HBV), and the mode of transmission is usually sexual transmission or unsafe injections or transfusions. The risk of vertical transmission of HBV infection is highest in neonates. The current treatment options for HBV include interferon injections and 5 oral agents. The preferred first-line therapy is entecavir-tenofovir (oral agents). Tenofovir is effective against lamivudine resistance, but entecavir is not. Without previous lamivudine treatment, both tenofovir and entecavir have high rates of viral suppression with minimal resistance. Lamivudine and telbivudine are second-line agents. Interferon is used less frequently in the United States than

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Intestinal Transplantation Outcomes Patient Survival Age group

1 year

5 years

18 to 34 years

81%

70%

35 to 49 years

80%

63%

50 to 64 years

93%

38%

65+ years

100%

N/A

From the Organ Procurement and Transplant Network (U.S.), 2002-2007

the oral agents. Pregnant women with a viral load over 108 copies are candidates for lamivudine, tenofovir, or telbivudine. HBV reactivation is common after chemotherapy/immunosuppression and can be fatal. Screening for hepatitis B surface antigen and anti-HBc proteins is essential in such patients, and long-term HBV prophylaxis should be considered. Finally, individuals with HBV DNA above 2000 IU and alanine aminotransferase levels above the upper limit of normal are candidates for therapy. Hepatitis C There are 170 million to 200 million carriers of the hepatitis C virus (HCV) worldwide, with 3 million to 4 million carriers in the United States. Currently, 25% of the HCV patients have cirrhosis. The greatest risk factors associated with acute HCV infection are injection drug use (43%) and other high-risk behaviors, along with exposure to infected blood. Two long-term followup studies of interferon treatment have demonstrated undetectable HCV RNA in 99% of patients after an average follow-up of 4.1 years and 5.6 years, suggesting that HCV is curable. In the United States, genotype 1 is the most common form of hepatitis C, followed by genotypes 2 and 3. Recently, it was reported that individuals with genotype 1 who were treated with pegin-

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terferon (peg IFN) and ribavirin and were carrying the CC allele on the IL28B gene showed a very high cure rate of 75% to 80% with a short treatment duration.28 The 2 new protease inhibitors, boceprevir and telaprevir, have been approved for genotype 1 HCV infection. These are administered in combination with peg IFN/ribavirin and have improved the response rate to 70%. For genotypes 2 and 3, the peg IFN/ribavirin therapy is the standard of care. It is important to consider drug-drug interaction before administering these drugs, because both strongly inhibit CYP3A4/5 and are partially metabolized by CYP3A4/5. Higher sustained virologic response rates have been reported in peg IFN/ ribavirin plus telaprevirâ&#x20AC;&#x201C;treated patients (75%) than in those treated with peg IFN/ribavirin alone (75% vs 44%; P < .0001).29 The side effects associated with telaprevir treatment are rash, anemia, drug-related eosinophilia, nausea, perianal symptoms, and diarrhea. Boceprevir plus peg IFN/ribavirin has been more effective for the treatment of patients coinfected with HCV/HIV than peg IFN/ ribavirin alone (61% vs 27%).30 Both drugs are effective in nonresponders (patients not responding to interferon). Anemia caused by boceprevir treatment is manageable.


What’s New in Pancreatic Disorders and Treatment Evan L. Fogel, MD, MSc, Professor of Clinical Medicine, reviewed the most current data related to pancreatic disorders and their treatment. The main clinical features of chronic pancreatitis include abdominal pain and exocrine and endocrine insufficiency. Pain management is achieved through medical, endoscopic, and surgical intervention. The commonly used surgical procedures are Whipple, Puestow, Frey’s, and Beger’s procedures. However, the procedure that is being used with increasing frequency is total pancreatectomy with auto-islet cell transplantation (TP-AIT). Patients undergoing surgery receive transplantation of native islet cells to prevent the risk of diabetes, which is directly related to the islet cell yield. Most patients have less pain after surgery, and 50% to 80% are narcotic independent at the 2-year to 4-year follow-up. Quality of life for pediatric patients after TP-AIT was significantly improved in a single-center prospective study of 19 children (aged 5-18 years, mean = 14.5) with chronic or acute recurrent pancreatitis.31 The study concluded that the majority of patients can be weaned off narcotic medications after surgery, and insulin independence (or minimal use) can be achieved in more than 60% of patients. Pancreatic divisum (PD) is a congenital abnormality of the pancreas, with a worldwide incidence of 7%. The vast majority of patients with PD are entirely asymptomatic. In patients who are symptomatic, minor papilla therapy, which enlarges stenotic orifices either endoscopically or surgically, improves symptoms in 75% to 80% of cases. Mutational analysis of control patients and patients with unexplained pancreatitis showed that the frequency of PD was no different in patients with idiopathic pancreatitis (5%), alcoholic pancreatitis (7%), and control patients (7%), but PD frequency was higher in patients with the genetic mutations PRSS1 (16%), SPINK1 (16%), and CFTR (47%). It was concluded that PD alone should no longer be considered an independent cause of pancreatitis, rather it acts as a cofactor in patients

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What I Tell Patients Regarding Treatment of Hepatitis C „„ HCV can be cured in 75% of all cases „„ T  herapy is evolving: about half of all genotype 1 individuals can be treated with 6 months of therapy „„ G  enotype 2/3 still has sustained viral response rates of >75% with peginterferon/ribavirin „„ IL-28 CC genotype will identify those who can be treated for shorter duration „„ Silymarin ... don’t bother with genetic mutations.32 However, the study suffered from the following limitations: the proportion of genetic mutations (PRSS1, SPINK1) in control populations is unknown, magnetic resonance cholangiopancreatography is not the gold standard for diagnosis of PD, and the coexistence of a genetic mutation with PD does not preclude other therapeutic options (ie, minor papilla therapy). Post-ERCP pancreatitis (PEP) is the most common major complication in 1% to 10%, as high as 30% of patients undergoing ERCP (endoscopic retrograde cholangiopancreatography). Reducing the pressure gradient across the pancreatic sphincter with a pancreatic duct stent may lower the frequency of this complication.33 Thus, temporary, smalldiameter PD stents lower the frequency and severity of post-ERCP pancreatitis in high-risk patients, and they are now considered standard care. The efficacy of various pharmacologic agents for prevention of PEP has been studied. Udenafil, a phosphodiesterase type 5 inhibitor, was not effective in the prevention of PEP.34 However, a meta-analysis supported the use of NSAIDs in the prevention of PEP.35 In this study, prophylactic rectal indomethacin was also shown to significantly reduce the incidence and severity of PEP in high-risk patients.

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Evaluation and Treatment of Pelvic Floor Disorders Diane M. Settles, MD, Assistant Professor of Clinical Medicine, gave a complete overview of pelvic floor disorders and an evaluation of available treatment options. The pelvic floor is a hammock made up of connective tissues, muscles, and neural structures. Symptoms of pelvic floor disorders (PFDs) include urinary incontinence (UI), pelvic organ prolapse, fecal incontinence (FI), and dyspareunia. It is still a question whether dyssynergic defecation is a symptom of true pelvic floor dysfunction. FI is the second most common reason for patients to be admitted to a nursing facility. A survey of 1961 women found that greater than 23% of women had at least 1 PFD; 15% had UI, 9% had FI, and 2.9% had pelvic organ prolapse. However, this may be an underrepresentation, because women are often embarrassed to report problems of incontinence. Pregnancy/delivery, parity, age, obesity, ethnicity, smoking, chronic pulmonary conditions, and menopause have been linked to PFDs. According to the National Health and Nutrition Examination Survey data, PFDs are more common among women who have had at least 1 child. In premenopausal women, parous women have


a higher prevalence of stress urinary incontinence and UI, and in postmenopausal women, parity has little effect on UI. Sphincter defects are associated with parity; however, anal sphincter defects are most commonly associated with the first pregnancy.36 A range of 7% to 60% of pregnant women experience UI and 6% experience FI. One mechanism of injury during pregnancy and childbirth is neural injury that can occur as a result of operative delivery, prolonged second stage of labor, or high birth weight. The second mechanism is anal sphincter disruption, which is associated with gross and occult injuries, role and risk of episiotomy, maternal birth position, and epidural use. According to a Cochrane Review of 21 studies performed to assess the role of elective cesarean in preserving maternal pelvic floor function, it was concluded that elective emergency cesarean surgery cannot be recommended for protecting anal continence. The evaluation of PFDs can be performed using different techniques. A physical examination is composed of a detailed neurologic examination, perianal inspection, and a detailed rectal examination that should include the assessment of resting and squeezing tone and attempted defecation. Manometric testing of anorectal abnormalities in patients with defecation disorders confirmed diagnosis in 90% of the cases, provided new information in 80% of cases, and influenced treatment in 84% of cases. Anal endosonography for the assessment of the thickness and integrity of sphincters, and pelvic magnetic resonance imaging for recognition of external anal sphincter atrophy are the other methods to evaluate PFDs. PFDs can be managed through lifestyle modifications, medications, Kegel exercises, biofeedback, surgery, sacral nerve stimulation, and artificial sphincters. Loperamide, lomotil, and codeine are the common medications used to reduce the frequency of incontinence. Hormone replacement therapy showed a 65% improvement in symptoms, and 25% of patients were asymptomatic after 6 months of treatment.37 Biofeedback has been shown to improve symptoms in 60% of the patients in

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a randomized controlled trial of 171 patients.38 Biofeedback is the mainstay of therapy in patients who fail to respond to supportive medication.

Diagnostic Testing in Inflammatory Bowel Disease Michael V. Chiorean, MD, Associate Professor of Clinical Medicine, Fellowship Program Director, described the most current approaches to diagnostic testing for inflammatory bowel disease, including their relative advantages and disadvantages. Calprotectin and lactoferrin are the 2 fecal biomarkers commonly used in the diagnosis of inflammatory bowel disease (IBD) in clinical practice. The advantages of these markers are that they are fairly sensitive and they provide a full bowel screen because signs of inflammation anywhere in the gastrointestinal tract will be reflected in the assays. These markers can detect inflammation in patients without an elevated C-reactive protein level or an elevated sedimentation rate. Assays are convenient because stool samples are routinely collected in IBD cases. They are also relatively inexpensive compared with other diagnostic tests ($40 and $60 for insurance payers). The disadvantage of using these fecal biomarkers is their nonspecificity; they may be elevated in patients using NSAIDs and those suffering from infections or malignancy. In a meta-analysis of pooled data from 30 studies including almost 6000 patients with established IBD, the sensitivity of calprotectin (threshold = 50 mcg/g - 100 mcg/g) was found to be greater than 90% and the specificity was 80% to 90%.39 In a metaanalysis of 6 studies of adults and children with suspected IBD and a pretest probability of 40%, the sensitivity and specificity of calprotectin were 93% and 96%, respectively.40 These data suggest that the use of calprotectin would prevent a large number of patients from undergoing further testing, and delayed diagnosis would occur in only 6% of the patients. Anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are the most extensively studied markers

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for diagnosing IBD. In a recent metaanalysis of 60 studies with almost 1000 patients, the ASCA and p-ANCA status was evaluated in patients with IBD versus patients with functional bowel disease.41 It was found that the sensitivity of a positive ASCA result with a negative p-ANCA result was approximately 60%. The specificity was not perfect (92%), and in a population with a low pretest probability, such as patients with nonspecific symptoms, this would lead to a substantial number of false positive results. p-ANCA seems to have a higher overall accuracy, and if a patient is both ASCA-positive and p-ANCA-positive, this provides some strength to the diagnosis because the specificity dramatically increases. However, few patients with IBD are both ASCA-positive and p-ANCA-positive. In previous studies, the correlation of calprotectin and lactoferrin with disease activity as measured by the endoscopic index has been shown to be similar, and these 2 markers seem to be better than Câ&#x20AC;&#x2018;reactive protein in predicting disease activity. In a study performed at Indiana University, a good correlation of fecal calprotectin with endoscopic disease activity in patients with both UC and Crohnâ&#x20AC;&#x2122;s disease was established.42 In summary, fecal inflammatory markers (calprotectin and lactoferrin) are useful in IBD diagnosis because they are sensitive and inexpensive, offer a full bowel screen, and can detect inflammation in patients without elevated Câ&#x20AC;&#x2018;reactive protein levels. However, their nonspecificity is a disadvantage. Serological markers (ASCA and p-ANCA) have modest specificity; however, their low sensitivity precludes their use in the diagnosis of IBD.

Best Use of 5-Aminosalicylates, Immunomodulatory Agents, Probiotics, Diet, Alternative Therapies in IBD Monika Fischer, MD, Assistant Professor of Clinical Medicine, reviewed the most current data on the treatment of IBD, including changing recommendations related to the use of 5-aminosalicylates. 5-aminosalicylates (5-ASAs) continue to be first-line therapy for ulcerative colitis


(UC). The American College of Gastroenterology IBD Task Force has strongly recommended 5-ASAs for the induction of remission in UC and to prevent relapse in quiescent UC. The recommendation is based on 11 high-quality randomized controlled trials, and the optimum dose of mesalamine is 2.4 g or the equivalent for both indications. Rare, but serious, side effects include interstitial nephritis, pancreatitis, pneumonitis, pericarditis, and hepatitis. Up to 8% of patients are 5-ASA intolerant. Once-daily dosing of 5-ASAs has been shown to achieve better compliance, higher efficacy, and better outcomes.43 The combined approach of oral 5-ASAs plus topical 5-ASAs as first-line therapy is highly effective in mildly severe to moderately severe active UC. The current recommendation suggests oral mesalamine plus topical mesalamine for inducing, as well as for maintaining, remission. However, 80% of patients favor oral treatment alone. Thus, patient preference highly affects drug adherence. Based on a meta-analysis of 3 randomized controlled trials of mesalamine (4g/d), 5-ASAs are no longer recommended for induction or maintenance of remission in Crohn’s disease. Although the prevention of colitis-related cancer by 5-ASAs has been actively studied, none of the previous studies have conclusively shown any impact of 5-ASAs on colitisrelated cancer risk. The common immunomodulatory agents used in the treatment of UC are the thiopurine analogs, azathioprine (AZA) and 6-mercaptopurine (6-MP), and methotrexate (MTX). AZA and 6-MP are recommended for maintenance, but not for induction of remission of UC. MTX is not recommended for UC induction or maintenance, but the recommendation is based on only 2 small studies. The efficacy rate of AZA in Crohn’s disease maintenance therapy after steroid (prednisolone) administration was 42% compared with 7% for placebo (P = .001).44 In the case of the addition of 6-MP treatment in children with active steroid-dependent Crohn’s disease, the duration of steroid use was shorter (P < .001) and the cumulative steroid dose required was lower (P < .01). Moreover, there was less relapse in the 6-MP group than in the placebo group (P = .007).45

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Underdosing of thiopurine analogs is a form of undertreatment, and dosages should be modified on the basis of thiopurine methyltransferase enzyme activity. Regular monitoring for myelosuppression is essential during thiopurine treatment. To achieve continuous remission, thiopurines should probably be continued indefinitely; withdrawal is associated with a high risk of relapse even after stable remission of several years. Evidence suggests that IBD is primarily caused by a dysregulated mucosal inflammatory response to intestinal bacteria in genetically susceptible individuals. The majority of currently used IBD therapies modulates the immune system. Therapies that modulate the gut flora may prove to be quite successful in the future. Dietary intake is related to the risk of developing IBD. However, there are no data to support diet as a form of treatment in Crohn’s disease and UC. Probiotics have great therapeutic potential in IBD management; however, the lack of evidence and the cost considerations have limited probiotics to adjuvant therapy only.

Best Use of Biologic Agents: Agent Selection, Monitoring, Dosing, and When to Stop Debra J. Helper, MD, Associate Professor of Clinical Medicine and Medical Director, Inflammatory Bowel Disease Center, discussed new developments in the treatment of Crohn’s disease, including recommendations for when to adjust treatment with specific agents by stopping, adjusting doses, or switching agents. The current FDA-approved drugs for moderate-to-severe, as well as refractory, Crohn’s disease are the IgG anti–tumor necrosis factor monoclonal antibodies infliximab, adalimumab, certolizumab pegol, and natalizumab. In terms of efficacy, adalimumab and certolizumab pegol show remission at weeks 20 to 30 compared with infliximab, which shows remission at week 4; however, the 3 agents appear to be basically equivalent in terms of their ability to induce remission. Their response rates range from 40% to 70%. The response and remission rates of

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natalizumab for Crohn’s disease at 10 weeks are 56% and 37%, respectively. In terms of durability, infliximab and adalimumab show a loss of response over time (13% and 20.3% per patient year, respectively). All 4 agents are intravenous infusions or subcutaneous injections, each with certain limitations. All have similar safety profiles and are associated with risk of infection, demyelinating disease, congestive heart failure, hepatitis, and lymphoproliferative disease. Infliximab and adalimumab can cause infusion-site reactions and lupus-like reactions. The Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) demonstrated that combination therapy of infliximab and azathioprine (2.5 mg/kg) was superior to that of infliximab or azathioprine monotherapy.46 Another study showed that the administration of hydrocortisone before infliximab infusion in patients with Crohn’s disease decreases the risk of developing antibodies to infliximab.47 A combined approach using infliximab, methotrexate, and sphincter-sparing surgery in patients with severe fistulizing Crohn’s disease was effective in achieving short-term response.48 Ciprofloxacin has also been used effectively in combination with infliximab in the treatment of fistulizing Crohn’s disease with an improved outcome: a response of 73% in the combination group versus 39% in the placebo group.49 Disease activity before and after therapy with biologic agents can be monitored by various tests, such as C-reactive protein, sedimentation rate, fecal calprotectin or lactoferrin, endoscopy, radiographic imaging, and capsule imaging. To monitor the biologic agent itself, in case of an increase in symptoms, parameters such as the trough levels and peak levels of infliximab, as well as the human antichimeric antibody/antibodies to infliximab levels, can be measured. There are no commercially available ways to monitor adalimumab or certolizumab pegol. Evaluations for tuberculosis, a complete blood count (at least once a year), and routine liver and kidney tests are common practice to monitor complications. The exception is natalizumab, which is associated with the complication of progressive multifocal leukoencephalopathy, for which an anti-


body test for JC virus is available. Based on previous studies, specific information on dosing is available, along with algorithms for dose adjustments and agent switching. The factors to be considered while stopping a biologic agent are reaction, infection, malignancy, neurologic symptoms, worsened congestive heart failure, skin lesions, and loss of response. All anti–tumor necrosis factor agents are category B drugs, except natalizumab, which is a category C drug. There has been no convincing evidence of adverse effects of biologic agents on the fetus to date. It is recommended that infliximab be withheld from week 30 of pregnancy, if possible, and be resumed after delivery. Overall, an individualized therapy is required for best disease control during pregnancy.

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32. Bertin C, Pelletier AL, Vullierme MP, et al. Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations. Am J Gastroenterol. 2012; 107(2):311-317. Epub 2011 Dec 13. 33. Choudhary A, Bechtold ML, Arif M, et al. Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review. Gastrointest Endosc. 2011;73(2):275282. 34. Oh HC, Cheon YK, Cho YD, et al. Use of udenafil is not associated with a reduction in post-ERCP pancreatitis: results of a randomized, placebo-controlled, multicenter trial. Gastrointest Endosc. 2011;74(3):556-562. Epub 2011 Jul 28. 35. Elmunzer BJ, Waljee AK, Elta GH, et al. A meta-analysis of rectal NSAIDs in the prevention of post-ERCP pancreatitis. Gut. 2008;57(9):1262-1267. Epub 2008 Mar 28. 36. Sultan AH, Kamm MA, Hudson CN, Thomas JM, Bartram CI. Anal-sphincter disruption during vaginal delivery. N Engl J Med. 1993;329:1905-1911. 37. Donnelly V, O’Connell PR, O’Herlihy C. The influence of oestrogen replacement on faecal incontinence in postmenopausal women. Br J Obstet Gynaecol. 1997;104(3):311-315. 38. Norton C, Chelvanayagam S, Wilson-Barnett J, Redfern S, Kamm MA. Randomized controlled trial of biofeedback for fecal incontinence. Gastroenterology. 2003;125(5):1320-1329. 39. von Roon AC, Karamountzos L, Purkayastha S, et al. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol. 2007;102(4):803813. Epub 2007 Feb 23. 40. van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ. 2010;341:c3369. 41. Reese GE, Constantinides VA, Simillis C, et al. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol. 2006;101(10):2410-2422. 42. Saad AM, Chiorean MV, Helper DJ, et al. The accuracy of fecal calprotectin for the diagnosis and assessment of disease activity in inflammatory bowel disease. American College of Gastroenterology, 2006. Abstract. 43. Dignass AU, Bokemeyer B, Adamek H, et al. Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7(7):762-769. Epub 2009 Apr 16. 44. Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995;37(5):674-678. 45. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology. 2000; 119(4):895-902. 46. Colombel JF, Sandborn WJ, Reinisch W, et al, for the SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395. 47. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124(4):917-924. 48. Roumeguère P, Bouchard D, Pigot F, et al. Combined approach with infliximab, surgery, and methotrexate in severe fistulizing anoperineal Crohn’s disease: results from a prospective study. Inflamm Bowel Dis. 2011;17(1):69-76. 49. West RL, van der Woude CJ, Hansen BE, et al. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn’s disease with infliximab: a doubleblind placebo-controlled study. Ailment Pharmacol Ther. 2004;20(11-12):1329-1336.

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