The May 2013 Digital Edition of Gastroenterology and Endoscopy News

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35th Anniversary — 2013

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gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 5 • May 2013

H E PAT O L O G Y IN F O C U S

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction

BY VICTORIA STERN

BOSTON—Recent evidence suggests that nonalcoholic fatty liver disease (NAFLD) is emerging as a significant public health problem. One study revealed an “alarming” rate of HCC related to NAFLD, even among

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28).

But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated.

The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation see HCV Screening, page 18

NAFLD Threatening Public Health

BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8

BY MONICA J. SMITH

Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA).

“This is very good news,” said Durado Brooks, MD, MPH, director of Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................page 16 Statins Linked to Reduction in Mortality From Liver Cancer.................................................page 24

see Cost Sharing, page 32 PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM

CLINICAL REVIEW see insert between pages 20 and 21

Ulcerative Colitis: Treatment Strategies

By Ellen J. Scherl, MD, Arun Swaminath, MD, Brian Bosworth, MD, and Vinita Jacob, MD

PRODUCT ANNOUNCEMENT

Ulcerative Collitis:

Optimizing Mesalamine Sttrategies ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

T

see page 63 for product information

he e greatest hallenge for ch

clinicians who

treat patients with inflamma atory bowel disease (IBD) is to move from symptomoriented (step--up) strategies toward preventio on-orie ented (early intervention) strategies aimed

ARUN SWAMINATH, MD

at tight inflammation control and alteration of the natural

Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

history of IBD. This review focuses on a personalized

BRIAN BOSWORTH, MD

acid (5-ASA) agents.

approach to the treatment of IBD using 5-aminosalicylic

Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

b

c

NewYork-Presbyterian Hospital/ Weill Cornell Medical Center New York, New York Weill Cornell Medical College New York, New York Columbia University College of Physicians and Surgeons New York, New York

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease.

One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

2013

1

FibroScan® Cleared by the FDA For Sale in the United States

Clean Freak

Effective cleansing in all bowel segments, including the right colon Percent of patients with NO RESIDUAL STOOL by colon segment1* Colon Segment

Cecum Ascending Descending Transverse Sigmoid/Rectum

SUPREP Bowel Prep Kit split-dose regimen (n=63) 91%† 91%† 92% 92% 94%

4-Liter Prep same-day regimen‡ (n=66)§ 67% 69% 84% 82% 81%

*This clinical trial was not included in the product labeling. †P≤0.02 vs 4-Liter Prep. Statistically significant difference. ‡ Standard 4-Liter Prep (sulfate-free PEG electrolyte lavage solution). § One patient was excluded who took the preparation but refused colonoscopy. Three patients had one or more segments that could not be evaluated because the procedure was stopped for poor preparation before cecal intubation.

SUPREP Bowel Prep Kit achieved “excellent” bowel cleansing in patients based on investigator grading1,2 • Split-dose regimens of SUPREP Bowel Prep Kit and MoviPrep®|| were equivalent in colon cleansing2 • Significantly more patients had “excellent” preps with SUPREP Bowel Prep Kit compared to MoviPrep (63% vs 53%, respectively; P=0.043¶)2 MoviPrep (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution) is a registered trademark of Salix Pharmaceuticals, Inc. ¶ Statistically significant difference. ||

Important Safety Information SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache.

Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes.

Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance.

Please see brief summary of Prescribing Information on adjacent page.

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

3

Can Hospital-Owned Practices Survive in the Long Run? Arthur Gale, MD Internal Medicine St. Louis, Missouri Contributing Editor, Missouri Medicine

[Editor’s Note: The following article was originally published in Missouri Medicine, January/February 2013;110:21.]

Doctors are becoming hospital employees.

Private practice, which has been the dominant way physicians have practiced since the country was founded, may be a thing of the past. Doctors are closing their offices for the simple reason that hospitals give them a hefty signing bonus for the first year or two, and the government and insurance companies reimburse them at higher levels as hospital employees than they can obtain in private practice. Hospitals buy doctors’ practices in order to lock

in referral sources for inpatient and outpatient services. How long can this costly state of affairs last?

The government is under tremendous pressure to reduce Medicare costs. Over the past 30 years, health care expenditures have increased from 7% to 16% of the gross national product (GNP). The number of uninsured people has increased from 30 to 50 million (Wikipedia, Health Care in the United States). For a family of

four, the cost of health care has increased to $20,000 annually according to a recent report from the Milliman Medical Index ((Am Med News, June 4, 2012). And the public is asking if all these expenditures are worthwhile. The health of the U.S. population is no better than the health of citizens of many countries that spend far less on health care than the United States.

Hospitals comprise the nation’s largest single health care expenditure, at about 30% of the total cost. Both the government and employers are finding it increasingly difficult to pay for skyrocketing health care costs. And they are finally beginning to scrutinize hospital costs.

Currently a mid-level office visit for a hospital-owned doctor is $124.40. The same visit in a private physician’s office is $69.97, or 44.6% less.

SUPREP Bowel Prep Kit. Because the quality of cleansing matters.

• Effective bowel cleansing2,3 in all bowel segments1

• Low volume

• ACG-recommended split-dose regimen

• No sodium phosphate

References: 1. Rex DK, DiPalma JA, Rodriguez g R, McGowan J, Cleveland M. A randomized clinical studyy comparing p g reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage g solution as ppreparation p for colonoscopy. py Gastrointest Endosc. 2010;72:328-336. 2. DiPalma JA, Rodriguez g R, McGowan J, Cleveland MvB. A randomized clinical study evaluatingg the safety and efficacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenteroll. 2009;104:2275-2284. 3. SUPREP Bowel Prep Kit [package insert].

Braintree, MA: Braintree Laboratories, Inc; 2010.

BRIEF SUMMARY: Before pprescribing, g please p see full Prescribing Information and Medication Guide for SUPREP® Bowel Prepp Kit (sodium sulfate, ppotassium sulfate and magnesium g sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. CONTRAINDICATIONS: Use is contraindicated in the followingg conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allergies g to components p of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prepp Kit is an osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. Use is contraindicated in the followingg conditions: ggastrointestinal (GI) obstruction, bowel pperforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allerggies to components of the kit. Use caution when pprescribingg for patients p with a historyy of seizures, arrhythmias, y impaired p ggagg reflex, regurgitation g g or aspiration p , severe active ulcerative colitis, impaired p renal function or ppatients takingg medications that mayy affect renal function or electrolytes. y Pre-dose and post-colono p scopy ECG’s should be considered in ppatients at increased risk of serious cardiac arrhythmias. y Use can cause temporary p y elevations in uric acid. Uric acid fluctuations in ppatients with ggout mayy pprecipitate p an acute flare. Administration of osmotic laxative products p mayy pproduce mucosal aphthous p ulcerations, and there have been reports of more serious cases of ischemic colitis requiring q g hospitalization. p Patients with impaired p water handlingg who experience p severe vomitingg should be closelyy monitored includingg measurement of electrolytes. y Advise all patients p to hydrate y adequately q y before, during, g and after use. Each bottle must be dilutted with water to a final volume of 16 ounces and ingestion g of additional water as recommended is important p to patient p tolerance. Pregnancy: g y Pregnancy g y Category g y C. Animal reproduction p studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive p capacity. p y Pediatric Use: Safetyy and effectiveness in ppediatric ppatients has not been established. Geriatric Use: Of the 375 ppatients who took SUPREP Bowel Prepp Kit in clinical trials, 94 (25%) were 65 years of age g or older, while 25 (7%) were 75 years of age g or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose p (2-day) y regimen g were observed between geriatric g patients p and yyounger g patients. p DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP mayy not be absorbed completely. p y ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal ppain, nausea, vomitingg and headache. Oral Administration: Split-Dose p (Two-Day) y Regimen: g Earlyy in the eveningg pprior to the colonoscopy: ppy Pour the contents of one bottle of SUPREP Bowel Prepp Kit into the mixingg container pprovided.

Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume onlyy a light g breakfast or have onlyy clear liquids q on the dayy before colonoscopy. py Dayy of Colonoscopy py (10 to 12 hours after the eveningg dose): Pour the contents of the second SUPREP Bowel Prepp Kit into the mixingg container provided. p Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least one hour prior to colonoscopy.y Consume only clear liquids until after the colonoscopy. STORAGE: Store at 20°-25°C (68°-77°F).

Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.suprepkit.com ©2012 Braintree Laboratories, Inc.

SU-13280T

January, 2012

An article published last year in the St. Louis Post-Dispatch ( June 14, 2012) listed the costs of magnetic resonance imaging (MRI) at various hospitals and outpatient imaging centers. There was at least a threefold difference in pricing. A private for-profit hospital was the least expensive. The largest hospital system in the area refused to reveal its prices for MRIs. Competition is supposed to be the hallmark of managed care, under which our current health system operates and which was supposed to reduce health care costs.

How can there be competition when there is no price transparency? Why does this marked disparity in hospital pricing exist?

MRIs aren’t the only overpriced hospital service. Hospitals strongly urge their employed physicians to refer their patients to hospital imaging centers for other types of x-rays and to high-priced, hospital-owned clinical laboratories and outpatient surgical centers.

Reimbursements Vary The influential governmental nonpartisan Medicare Payment Advisory Commission (MedPAC) has recommended cuts in hospital reimbursement. One major cut would be in primary care services. Currently a mid-level office visit for a hospital-owned doctor is $124.40. The same visit in a private physician’s office is $69.97, or 44.6% less. MedPAC has recommended the elimination of this disparity ((Am Med News, March 26, 2012).

MedPAC has recommended uniform see Hospitals, page 4

4

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Hospitals continued from page 3

pricing for identical treatments, regardless of whether they are administered by doctors who own their own practices or doctors who work for hospital-based clinics. It is estimated that this change alone would save Medicare about $1 billion per year. If implemented, it would also severely hamper hospitals’ ability to attract physician employees.

How did it come about that the government and insurance companies pay doctors in private practice so little but pay hospital-based doctors so generously?

Both the Federal Trade Commission and corporate managed care organizations have encouraged hospitals and health plans to employ physicians. Policymakers hold as an article of faith that conflicts

of interest inherent in fee-for-service private practice are the root cause of high health care costs.

The “experts� contend that cost savings can be realized when physicians practice as employees in vertically integrated systems like Mayo Clinic, the Cleveland Clinic, Kaiser Permanente and other hospital systems. There are no studies to support this assumption. In fact the data, some of which are cited above, support the opposite conclusion.

What percent of the GNP does health care have to consume before policymakers start making changes in hospital reimbursement? When will hospitals be held accountable for their lavish spending on massive unnecessary building

programs, huge administrative salaries, advertising, and yes, even subsidies to physicians? And when will the so-called experts in health care admit that multihospital mergers and the ownership of physician practices function as monopolies that raise, not lower, costs?

The average physician rushing to sell his or her practice to a hospital doesn’t have time to think about these questions.

There are bills to pay, children to send to college, mortgage payments to meet and savings to put away for retirement.

Possibilities for Change But sooner or later, the good times for hospitals will have to end. The hospitals will of course vigorously oppose any

changes in the current system. Congress is not bound to accept the recommendations of MedPAC. Hospitals constitute a very powerful lobby and will use all of their vast resources to maintain the status quo. Economic reality may nevertheless force them to cut back on nonessential expenses.

If third-party payers and the government decide to pay physicians owned by hospitals at the same rate that they pay physicians in private practice (as MedPAC recommends), physicians may find becoming a hospital employee less attractive. And hospitals might be forced to lay off many of their employed physicians. If such a scenario plays out, private practice could make a comeback. â–

Vol. 64, No. 5

MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, BSC, MS, PHD, DSC

Farmington Hills, Michigan

FREDRIC DAUM, MD Mineola, New York

STEVEN M. FABER, MD Elizabeth City, North Carolina

Sacramento, California

PETER R. MCNALLY, DO Fort Carson, Colorado

TARUN MULLICK, MD St. Charles, Illinois

RONNIE FASS, MD Cleveland, Ohio

BARBARA B. FRANK, MD Philadelphia, Pennsylvania

EDITORIAL STAFF

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MAUREEN SULLIVAN, Associate Editor, msullivan@mcmahonmed.com DAVID BRONSTEIN, KEVIN HORTY, ADAM MARCUS, GABRIEL MILLER, DONALD M. PIZZI, SARAH TILYOU,

JOEL E. RICHTER, MD Tampa, Florida

DAVID ROBBINS, MD New York, New York

FRANK G. GRESS, MD

ELLEN J. SCHERL, MD

Brooklyn, New York

New York, New York

CHRISTOPHER JOLLEY, MD

PRATEEK SHARMA, MD

Gainesville, Florida

Kansas City, Kansas

MYRON LEWIS, MD

JEROME H. SIEGEL, MD

Memphis, Tennessee

New York, New York

Contributing Editors JAMES PRUDDEN, Group Editorial Director

MATTHEW SPOTO, Senior Account Manager, mspoto@mcmahonmed.com ALINA DASGUPTA, Junior Sales Associate, Classified, adasgupta@mcmahonmed.com

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May 2013

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INFECTIOUS DISEASE SPECIAL EDITION

1CAB=; ;327/

LETTER TO THE EDITOR

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

5

Guidelines on GERD Surgery, Courtesy of SAGES Re: “Number of Antireflux Surgeries at Low-Volume Centers Grows, Despite Worse Outcomes,” by Ted Bosworth. Gastroenterology & Endoscopy News April 2013;64:38-39.

I am writing to respond to an article in your April 2013 issue titled “Number of Antireflux Surgeries at Low-Volume Centers Grows, Despite Worse Outcomes,” by Ted Bosworth. In the article, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) is referenced and it is implied that the organization should create standards that have not yet been set, when in fact, SAGES has already established such guidelines.

Specifically, the article states: “Why not establish standards for individual surgeons and hospitals regarding the volume of antireflux surgery that should be performed on a yearly basis to maintain competency?”

Dr. [ Joel] Richter asked. “Frankly, this is an issue that the surgical societies like SAGES should address.”

According to Robert D. Fanelli, MD, chief of minimally invasive surgery and surgical endoscopy at Guthrie Clinic, in Sayre, Pa., and chair of the SAGES Guidelines Committee, SAGES addressed the learning curve associated with performing high-quality laparoscopic antireflux surgery in its February 2010 “Guidelines

for Surgical Treatment of Gastroesopha- a minimum threshold, but that mentoring of Laparoscopic Surgery Curriculum,” geal Reflux Disease (GERD),” published by more experienced surgeons during a an important educational program supin Surgical Endoscopy (Stefanidis D et al. surgeon’s first 15 to 20 laparoscopic anti- porting laparoscopic competency that is 2010;24:2647-2669) and on the SAGES reflux procedures was supported in some completed by all general surgery residents website (www.sages.org/publications/ of the literature studied and is presented during their training. guidelines/guidelines-for-surgical-treat- in this guideline.

SAGES clinical practice guidelines ment-of-gastroesophagealand position statements can be reflux-disease-gerd). These accessed on the SAGES webguidelines advise surgeons, SAGES’ “Guidelines for Surgical Treatment site at www.sages.org/publicagastroenterologists and othtions/guidelines.

■ of Gastroesophageal Reflux Disease (GERD)” ers involved in the evaluaMary Cohen tion and treatment of patients advises surgeons, gastroenterologists and Director of PR & Marketing, with GERD on appropriate others involved in the evaluation and treatment SAGES patient selection, evaluation Los Angeles, Calif. of patients with GERD on appropriate patient and treatment selection.

The SAGES Guideline selection, evaluation and 35th Anniversary recommends that: treatment selection.

“Surgeons with little experience in advanced laparoscopic techniques and fundoplication in SAGES offers a host particular should have expert supervision of guidelines pertaining during their early experience with the to clinical practice, eduDefending Against Malpractice: Food Allergy Steps To Winning a Lawsuit procedure ...” and that “reoperative anti- cation and training, and Explored in IBS Start Before It Beg gins reflux surgery should be performed in a credentialing that provide high-volume center by an experienced guidance to surgeons and foregut surgeon.” institutions.

AdditionDr. Fanelli said that the committee ally, SAGES has creBinge Drinking Linked to IBS found no clear-cut numerical standard for ated the “Fundamentals 1978 —

— 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

BY CHRISTINA FRANGOU

BY MONICA J. SMITH

Allergies to foods or food additives may contribute to the pathogenesis of irritable bowel syndrome (IBS)– like symptoms, according to a recent study published in the Journal of the American Academy of Dermatology (Stierstorfer MB et al. 2013;68:377-384). see Allergies, page 14

Symptoms

BY BRIGID DUFFY

Binge drinking may worsen gastrointestinal (GI) symptoms in women with irritable bowel syndrome (IBS), according to a study published in the February issue of the American Journal of Gastroenterology (Reding KW et al. 2013;108:270-276).

Allergic Reaction in the Gut Hypothesized in IBS

A recent study found that, over a 40-year career, docctors spend an average of 11% of their time dealing with un nresolved, open malpractice suits (Seabury SA et al. Health Aff 2013;32:111-119). But there are steps that physi-cians can take to reduce the risk for malpracticee suits, to manage the complications that may lead too them and to increase the likelihood of winning a casee should they be faced with one.

“There are things you can do ahead of time— — things you can do during the procedure and afteer the event—that you need to know about,” said Joh hn Baillie, MB, ChB, director of medical gastroenteroology, Carteret General Hospital, Morehead City, N.C. Dr. Baillie said that physicians must know the national standards for endoscopic practice that are available on gastroenterology society websites and acceessible to non-members.

“In the event of a malpractice litigation, the plaintiff ’s intent is to show that the physician has deviated froom the standard of care, [defined as] what a reasonable physician would have

see Alcohol, page 14

see Malpractice, page 26

I N S I D E

EXPERT ROUNDTABLE

EXPERT REVIEW

Therapy for Barrett’s Esophagus

Re: “Food Allergy Explored in IBS,” by Christina Frangou.

Gastroenterology & Endoscopy News April 2013;64:1,14.

What, When and in Which Patients?

W

BY MAUREEN SULLIVAN O ver the past decade, new advancements in ablation therapy have Ove exxpaanded treatment options for patients with Barrett’s esophagus (BE).

Introoduced to clinical practice in 2005, radiofrequency ablation (RFA) is on ne of the most recent ablation techniques available for the treatment see Barrett’s Esophagus, page 18

Fecal Microbial Transplantation: An Increasingly Important Alternative for the Treatment of C. difficile .................................................................................. page 6

Allen Kamrava, MD, MBA

Gary H. Hoffman, MD

Pancreatic Exocrine Insufficiency

We are pleased that Dr. William D. Chey expressed interest in our work. Our study was a proof-of-concept study. The concerns that Dr. Chey raised mirror those we listed as limitations of the study in our report and need to be addressed for validation of the concept. The following may address some of the concerns.

We had patients avoid the foods to which they had positive patch tests for one week, as we felt it would be difficult to ask them to avoid the foods for much longer, especially if there was no improvement after one week. We were confident that one week would be long enough to determine whether there would be improvement based on prior observations we had made.

We shared the concern about placebo effect. Of the 14 patients who benefited during the study, we had the opportunity three months or more after the study to ask 11 of them how they were doing. Ten of those patients maintained improvement while continuing dietary avoidance for three months or longer. The one patient who did not sustain improvement was a woman who reported slight improvement in the study with sodium benzoate avoidance; however, she reported that sodium benzoate was not part of her routine diet. We feel that continued improvement for the other 10 patients makes a placebo effect unlikely, although this was not reported as it was not part of the original study protocol.

One of the most dramatic results in the study was a woman who had a positive patch test to limonene, which is in citrus. When asked if she ate citrus regularly, she reported drinking tea with lemon every night. She stopped the lemon and improved greatly, and improvement was sustained at the three-month follow-up. Another patient reported similar success after avoiding dodecyl gallate, a preservative. Her sensitivity to the preservative would have been essentially impossible to determine without the testing.

As for blinding the study patients, if anyone has a good idea of how to do that, please let us know! I think it would be fairly impossible to blind people to be sure they are avoiding a specific food for several weeks, unless they were placed under 24-hour supervision.

As for including patients who had gastrointestinal symptoms suggestive of irritable bowel syndrome (IBS) but not enough to fit the diagnostic criteria, or who did not have physician-diagnosed IBS, we feel (and felt) such testing could benefit them and thus included them in this proof-of-concept study. A more formal validation study for IBS would require more restrictive entry criteria.

As for needing more foods and food allergens, we agree. For the study, we chose food allergens that were most readily available and within the budget of our

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Now for sale at www.McMahonMedicalBooks.com

By Vivek Kadiyala, MD, Shadeah Laila Suleiman and Darwin L. Conwell, MD, MS

Part 1 of 2: Treatment Approaches VIVEK KADIYALA, MD SHADEAH LAILA SULEIMAN DARWIN L. CONWELL, MD, MS Center for Pancreatic Dis isease s Brigham and Women’s Hospital Division of Gastroenterol ology, Hepatology, and Endo oscopy Harvard Medical School Boston, Massachusetts

self-funded study. The types of foods we used are all known to cause type 4 (poison ivy–like) Web allergic skin reactions.

Comment We hypothesize the same type of reaction is occurring in the intestine, as the immune system has just as much access to the intestine as to the skin—maybe more because the intestine, unlike the skin, has no stratum corneum to protect it. We have since been working with universitybased food scientists and compounding pharmacists to develop many more of these types of foods and food additives into a patch test–ready form, and now have nearly 120 ready for patch testing.

Anyone interested in more information, including how we became interested in this work, may contact me.

Michael Stierstorfer, MD East Penn Dermatology, PC North Wales, Pa. Via website April 9, 2013

I

n Part 1 of this 2-part review, treatment approaches for patients with pancreatic enzyme insufficiency

(PEI) are covered, including the proper use of currently FDA-approved pancrelipase preparations.

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS • A P R I L 2 0 1 2

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

From the Literature

Ibuprofen Aggravates Exercise-Induced Intestinal Injury, Permeability

BY BRIGID DUFFY Consumption of ibuprofen by healthy athletes can aggravate exerciseinduced injury of the small intestine and cause gut barrier dysfunction, leading to gastrointestinal trauma in otherwise healthy individuals, according to a study published in Medicine & Science in Sports & Exercise, a research journal of the American College of Sports Medicine.

The study (Med Sci Sports Exerc 2012;44:2257-2262), led by Kim van Wijck, MD, of the Department of Surgery, Maastricht University, the Netherlands, was a follow-up to an experiment Dr. van Wijck published in 2011 (PLoS One 2011;6:e22366).

In that study, she and her colleagues concluded that after an hour of hard cycling, cells lining the intestines of the healthy men who participated in the experiment were starved of blood and became permeable, an indication of gut barrier dysfunction.

In light of the proclivity for many

athletes to take ibuprofen before exercise in an attempt to mitigate anticipated muscle soreness, Dr. van Wijck set out to determine the combined effect of exercise and ibuprofen, the first study of its kind.

To this end, Dr. van Wijck’s team recruited nine active, healthy men who were studied on four separate occasions. During two of the visits, study participants laid supine for one hour, once without consuming ibuprofen and once after taking 400 mg of ibuprofen the night before the study and another 400 mg one hour before visiting the lab. In two subsequent visits, the men briskly rode stationary bicycles for one hour, again taking 400 mg of ibuprofen the night before and the morning of one of those workouts.

At the end of each session, researchers assessed small intestinal injury and gastrointestinal permeability. It should be noted that neither hydration status nor renal function were measured, factors that might

contribute to intestinal compromise.

The researchers found that, as predicted, blood levels of intestinal fatty acid–binding protein, a marker of intestinal leakage, were much higher when the men combined vigorous exercise with ibuprofen than during the other experimental conditions.

This is worrisome, according to Dr. van Wijck, as intestinal leakage could have serious consequences, including the subsequent translocation of bacteria and the permeation of harmful digestive enzymes into the bloodstream.

James Scheiman, MD, professor in the Department of Internal Medicine at the University of Michigan, Ann Arbor, concurred that intestinal leakage has the potential to lead to significant problems, such as loss of blood and anemia. However, Dr. Scheiman pointed out that the vast majority of endurance athletes who consume reasonable amounts of ibuprofen are not in danger.

“This is a case of relative risk versus

absolute risk,” Dr. Scheiman noted.

“We know that decreased blood flow to the intestine occurs with intense exercise. We know that ibuprofen exacerbates that. The perception that NSAIDs [nonsteroidal anti-inflammatory drugs] have no risk is simply not true. But how important is that? We’re not seeing an epidemic. The body is able to respond and repair in the vast majority of patients.”

Although the study indicates that ibuprofen is not risk-free, even in healthy athletes, Dr. Scheiman noted, “It’s a matter of compromise.”

■

True Resistance to Enteric-Coated Aspirin Not Likely, Researchers Say Pseudoresistance Common With Enteric-Coated, But Not Immediate-Release, Aspirin enteric-coated aspirin (81 mg) and clopidogrel (75 mg), each for one week, to assess whether their resistance was specific to aspirin or encompassed A study published earlier this year investigated clopidogrel, another platelet inhibitor. All subjects whether resistance to low-dose aspirin—taken responded to aspirin on repeated exposure, addito reduce the secondary incidence of myocar- tion of aspirin to their platelets ex vivo or lengthendial infarction and stroke—may be caused by ing of the post-dosing interval. the enteric coating that is widely used in aspirin The authors concluded that true aspirin resisproducts to reduce harm to the gastric mucosa tance is rare; in fact, they failed to find a single (Grosser T et al. Circulation 2013;127:377-385). case of true drug resistance.

In the study, 400 healthy volunteers, all of whom “It did surprise us,” said first author Tilo Grosser, received a single oral dose MD, research assistant proof 325 mg of aspirin, were fessor of pharmacology, divided into three groups: ‘There is no reason to take enteric Institute for Translational Group 1 (n=40) received regMedicine and Therapeutics, coating; it renders the drug effect ular, immediate-release aspiUniversity of Pennsylvania, rin, with response assessed more erratic. There’s no benefit.’

Philadelphia. eight hours after dosing; The authors found that —Tilo Grosser, MD group 2 (n=210) received pseudoresistance, resulting enteric-coated aspirin, with from delayed and reduced response also assessed at eight hours; and group drug absorption, commonly occurred with enteric3 (n=150) received enteric-coated aspirin, but with coated, but not immediate-release, aspirin. The response assessed at four hours. results support previous findings of inconsistent According to the study authors, all the subjects platelet inhibition after the use of enteric-coated in group 1 responded “with a reduction of platelet aspirin. aggregation—induced by direct stimulation of the David A. Johnson, MD, professor of medicine COX-1 (cyclooxygenase-1) pathway by arachi- and chief of gastroenterology, Eastern Virginia donic acid—by >60% comparing pre- and post- Medical School, Norfolk, who was not involved in dose measurements.” In contrast, in Group 2, 17% the current study, noted, “An enteric-coated aspiwere nonresponders, and in Group 3, 49% were rin is not any safer than a regular aspirin. It may nonresponders. have fewer clinically reported side effects of dysIf subjects appeared aspirin-resistant, they pepsia or abdominal pain, but not be safer from underwent repeat testing, and if they still a gastroenterological perspective as it relates to seemed resistant they were given a low dose of gastrointestinal [GI] complications of bleeding,

BY GEORGE OCHOA

obstruction or perforation.

“In studies, GI complications of ulcers are higher with enteric coating, but this may reflect a stratification bias of use in higher-risk patients,” explained Dr. Johnson, who is a past president of the American College of Gastroenterology.

Dr. Grosser explained: “Enteric-coated aspirin was developed to reduce GI toxicity by reducing direct contact with the stomach wall. The problem is that aspirin circulating in the bloodstream will also damage the stomach. So, even with the coating, aspirin will increase the risk for ulceration.

“No epidemiologic study has found a reduction of bleeding risk,” Dr. Grosser added. “It’s not validated that it’s safer for the stomach. … There is no reason to take enteric coating; it renders the drug effect more erratic. There’s no benefit,” he concluded.

He added that the major limitation of the study was that the subjects were healthy individuals.

Also, “we lost a number of subjects to followup,” he said.

Dr. Johnson noted that a prospective study should be undertaken to confirm the findings.

“The [study] needs to be validated by a prospective study: enteric coating versus non-enteric coating, with secondary prevention of myocardial infarction and stroke as end points.”

■ Dr. Grosser has served as a consultant on projects related to aspirin but not aspirin resistance. The present study was partially funded by Bayer and the National Institutes of Health, but neither had a say in the study design or data analysis and interpretation, Dr. Grosser said. Dr. Johnson reported no relevant financial conflicts of interest.

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Investigational Device Prolongs Survival Of Livers for Transplantation May Increase Availability of Donor Livers

BY VICTORIA STERN Patients who need a new liver to survive must hope that they are one of the approximately 13,000 liver transplant recipients in the United States and Europe each year. But with 30,000 people on waiting lists, and with only ice keeping livers for transplantation viable for up to 14 hours, the odds are not always in the patients’ favor. Each year, more than 2,000 livers don’t survive the journey to their new home.

“Preserving organs by cooling them down is far from perfect,” said Peter J. Friend, MD, director of transplantation surgery, Nuffield Department of Surgical Sciences, Oxford Transplant Centre, U.K. “Although cooling the organ on ice slows its metabolism by a factor of 10, the liver continues to metabolize slowly and deteriorates as a result. It’s hard to tell which organs will work and which ones won’t.”

Now, however, Dr. Friend and his colleeague Con n stantin Coussios, PhD D, professor of biiomedical engineeriing at the University of O Oxford, f d h have d devised i d a novell technology that may be a game changer: A machine that allows the liver to function for up to 24 hours, as though it were still inside a human body.

On March 15, the team of engineers and physicians announced the preliminary success of this machine, which has safely transported livers to two transplant recipients at King’s College Hospital in London.

“The first two cases went very well,” said Dr. Friend. “They weren’t exceptionally high risk, but the machine did what it was supposed to do.”

A liver 30 seconds after connection to the OrganOx Metra device; parts of the organ are still cold, while other parts are warm and perfused with red cell solution.

The liver 5 minutes after connection to the OrganOx Metra, now fully perfused and at physiologic temperature.

other chemicals to create a physiologic environment that mimics the human body. The liver is not only kept alive, but it continues to produce bile as well.

Additionally, the machine is compact.

“It’s about the size of a supermarket trolley [shopping cart], which means it can go in back of ambulance, small plane or helicopter,” Dr. Friend said. “Size was very important because we knew there was no point in making a machine if it couldn’t fit in the back of a vehicle.”

Long Time in the Making

‘Although cooling the organ on

In 1994, Drs. Friend and Coussios devised the idea for the technology, but faced several engineering challenges while developing it. The co-inventors needed to create an artificial environment, which could simulate the key functions of the human body, including pumping blood and providing nutrition to the organ. These functions not only had to be automated to make it possible for transplant surgeons around the globe to use the technology, but also small enough for easy transportability.

After 15 years of developing and tweaking the design, Drs. Friend and Coussios have created a technology that appears to meet these requirements.

The liver’s main blood vessels are connected to tubes on the machine, which automatically regulate the environment around the liver. The device maintains the liver at body temperature and infuses it with oxygenated red blood cells, nutrition, such as glucose and amino acids and

ice slows its metabolism by a factor of 10, the liver continues to metabolize slowly and deteriorates as a result. It’s hard to tell which organs will work and which ones won’t.’

—Peter Friend, MD

Notably, the machine also may allow the liver to recover from injuries it sustained during or before removal, Dr. Friend pointed out. This function of the device is particularly important because it could expand the number of viable livers for transplantation. In recent years, the demand for livers has grown, as liver disease has become more common, whereas the quality of donor livers has diminished.

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY MAY 2013 2013

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Effect of Preexisting Cardiovascular Disease on Outcomes After Liver Transplantation May Be Underestimated, Researchers Say

BY TED BOSWORTH

All photos courtesy of the University of Oxford

LAS VEGAS—Preexisting coronary artery disease (CAD) appears to have a far greater adverse effect on outcomes after liver transplantation than previously recognized.

In data collected on more than 600 patients, the rate of cardiovascular (CV)-related death was five times higher among patients who had a revascularization procedure before liver transplantation than among those who did not. The rate of major adverse cardiac events (MACE) in this population was eight times higher. The rates of MACE also increased in a stepwise fashion with increasing severity of pretransplant CAD as assessed by angiography.

“CAD is emerging as the leading cause of non–graft-related death after liver transplantation,” reported Mazen J. Albeldawi, MD, of the

Department of Gastroenterology and Hepatology, transplantation, he noted, but climbs steeply in Cleveland Clinic, Ohio, who collaborated on the patients with preexisting diseases. study with senior investigator Nizar N. Zein, MD, Dr. Albeldawi and his colleagues evaluated the and presented the findrisk for CV events in 652 ings at the annual meeting patients who underwent of the American College of ‘CAD is emerging as the leading liver transplantation durGastroenterology. ing a 12-year period at the cause of non–graft-related death The high rates of MACE after liver transplantation.’

Cleveland Clinic. Of these, and death related to CAD 339 patients were referred —Mazen J. Albeldawi, MD for a myocardial perfusion in the transplant population suggest a need to “examstudy and 75 underwent ine what should be considered an acceptable cardiac catheterization. CAD was angiographimortality and morbidity risk,” Dr. Albeldawi said, cally proven in 43 patients (7% of the total popnoting that a substantial proportion of CAD deaths ulation). The incidence of MACE (one or more occur in patients with a functioning graft. He sug- events) over the course of follow-up was 28% gested these data might deserve attention in the in those with proven CAD, ranging from 21.9% absence of guidelines that establish levels of CV in those with single-vessel disease to 31.6% in risk that should weigh in the decision of selecting those with multiple-vessel disease. The median candidates for transplantation. time to an event was 20.1 months.

The risk for MACE is already high after liver see CAD, page 12

The King’s College Hospital, Oxford University and OrganOx team successfully connects the first human liver for transplantation to the OrganOx Metra device.

“More and more, donors tend to be older, and have a high body mass index or coexisting major health problems,” Dr. Friend noted. “Because of the increasing demand for livers, we are having to use organs we would have once said no to.”

Now with the machine, transplant surgeons can test how well the liver is working during preservation.

“If the liver works on the pump, then we can assume it will work in the recipient,” said Maria B. Majella Doyle, MD, MBA, associate professor of surgery at Washington University School of Medicine, St. Louis, who specializes in liver transplantation. Dr. Doyle was not involved in developing this pump, but she is performing research to develop a

different liver pump system, one that also keeps the liver at physiologic temperature.

‘If the machine is as good as we believe, we would expect a significant increase in patients who get liver transplants.’

—Peter Friend, MD

In April 2008, Drs. Friend and Coussios cofounded a company called OrganOx Ltd., to continue their University of Oxford research. With financial

The OrganOx Metra device

support from the Royal Society and several venture capital funds in the United Kingdom, the company has been working to bring the technology to patients.

Although promising, the device still needs more testing. The U.K. team has begun a pilot trial at King’s College Hospital to test the ability of the machine to transport livers to 20 transplant patients.

If the trial is successful, OrganOx could then apply for marketing authority, which would make the device commercially available in Europe.

“If the machine is as good as we believe, we would expect a significant increase in patients who get liver transplants,” Dr. Friend said.

According to Dr. Doyle, the group is

“ahead of the game.” To her knowledge, two other teams are developing physiologic-temperature liver pump systems— Dr. Doyle and her colleagues William Chapman, MD, and Vijay Subramanian, MD, at Washington University, and Constantino Fondevila, MD, PhD, at the University of Barcelona—but both are at more preliminary stages.

“The U.K. team is the first to produce human data with the pump and show it’s safe and viable as a liver transplantation device. Now, it’s important to make sure the technology is foolproof and cost effective,” Dr. Doyle said.

“The U.K. team needs to be highly commended. The pump is a great achievement.”

■

References: 1. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.

Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:1559-1574. 2. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet. 1998;352(9130):799-805.

What’s behind the symptoms?

Carcinoid Syndrome Can Be Deceptive Early diagnosis of carcinoid syndrome is essential.

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

No Increased Benefit Observed With Doxorubicin-Eluting Beads for Hepatic Artery Embolization in HCC

BY CHRISTINA FRANGOU SAN FRANCISCO—A randomized trial showed no benefit to using doxorubicineluting beads over conventional bead block for hepatic artery embolization in the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Using the Response Evaluation Criteria in Solid Tumors (RECIST) rules—which define when cancer patients improve (i.e., “respond”), stay the same (i.e., “stable”) or worsen (i.e., “progression”) during treatments—researchers found that patients who received the drug-eluting beads had an overall response rate of 9% compared with 11% for patients in the drug-free arm. The difference was not statistically significant, according to lead author Karen T. Brown, MD, an interventional radiologist at Memorial Sloan-Kettering Cancer Center in New York City.

There were no improvements in median time to progression, progression-free survival (PFS) or overall survival (OS) with the doxorubicin beads compared with the standard bead block, the researchers reported.

Dr. Brown said the study “brings into question the added benefit of

chemotherapy for embolization of hepatocellular carcinoma.”

Two studies published more than a decade ago provided the first evidence that transarterial embolization for the treatment of HCC improved OS compared with best supportive care (Lo CM et al. Hepatologyy 2002;35:1164-1171; Llovet JM et al. Lancett 2002;359:17341739). Some people interpreted the findings of the Lancett study to mean that chemoembolization produced a survival benefit. However, the study was stopped too early to show any significant difference between transarterial chemoembolization (TACE) and embolization alone, leaving questions about which treatment—if either—was superior. Despite this, TACE has become the “most widely used locoregional therapy for patients with intermediate to advanced HCC,” according to a 2010 report in The Oncologistt (Lencioni R et al. 2010;15:42-52).

In the current study, presented at the 2013 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, investigators recruited 101 patients with unresectable Okuda stage I-II HCC and randomized them to receive embolization or embolization with beads loaded with 150 mg of doxorubicin.

CAD continued from page 9

Like multiple-vessel disease, the severity of stenosis also predicted MACE, climbing from 20.7% among those with mild disease, defined as stenosis of less than 50%, to 31.2% in those with greater involvement, according to Dr. Albeldawi. Relative to disease in lesser vessels, stenosis in the left anterior descending or right coronary arteries also predicted an increased risk for MACE. Patients who had undergone a revascularization procedure—whether coronary bypass grafting or percutaneous transluminal coronary angioplasty— fared the worst. In these individuals, the risk for all-cause mortality was twice as high as in those who had not undergone a pretransplant revascularization procedure, a rate that reached statistical significance ((P=0.049).

The elevated rate of CAD following liver transplantation is already well known. At the Cleveland Clinic, the protocol for evaluation before liver transplantation already includes echocardiography in all patients. Dobutamine stress echocardiography is performed in patients older than 50 years of age or in those who have multiple CV risk factors, whereas cardiac catheterization is performed in those who demonstrate stress-induced ischemia or in patients who have a history of CAD. However, these data suggest the rates, already high in individuals with

The study ‘brings into question the added benefit of chemotherapy for embolization of hepatocellular carcinoma.’

—Karen T. Brown, MD

Patients were evaluated with multiphasic computed tomography [CT] scans at two to three weeks post-treatment, and with CT scans every three months until progression of disease or death.

Demographics of the two groups were comparable. Patients had a median age of 67 years, 77% were men and 81% were classified as Okuda stage I. The median number of embolization procedures was two for both arms.

The two-year probability of PFS was low in both groups. Median PFS among patients treated with the bead block was 5.2 months, slightly better than the 4.6 months in patients who received doxorubicin-containing beads (P=0.38).

P The difference was not statistically significant.

mild disease, climb to levels that may be unacceptable in those at highest risk.

Krista Lentine, MD, MSc, associate professor of internal medicine, St. Louis University School of Medicine, Missouri, agreed that these findings “resonate with past demonstrations of high morbidity and mortality in liver transplant recipients with CAD,” but she also suggested that CV risk should not be considered in isolation of the indications for liver transplantation.

‘A critical consideration extends beyond relative outcomes among liver transplant candidates with varying [CV] risk profiles to post-transplant outcomes compared with care without transplantation.’

—Krista Lentine, MD, MSc

“It is important to recognize that liver transplantation is the only lifesaving therapy for patients with end-stage liver disease consistently associated with improved survival, and there is no alternative form of liver replacement therapy analogous to dialysis for patients with kidney failure,” noted Dr. Lentine, who was lead author of a recent scientific

OS also was similar: The bead block was associated with a median 16.6-month survival, and the drug-eluting beads with a median survival of 19.6 months (P=0.83).

P Ahmed O. Kaseb, MBBS, director of the HCC program at the University of Texas MD Anderson Cancer Center in Houston, cautioned that the study is too small to change clinical practice but warrants larger validation studies.

“It’s an important study that addresses the current standard practice of TACE for patients who are not surgical and yet have localized HCC to their liver.”

Investigators pointed out that the drug-eluting beads did not increase the risk for post-embolization syndrome or major adverse events.

■

statement by the American Heart Association (AHA) on cardiac evaluation in liver and kidney transplantation candidates (Lentine et al. J Am Coll Cardiol 2012;60:434-480). “Thus, a critical consideration extends beyond relative outcomes among liver transplant candidates with varying risk profiles to post-transplant outcomes compared with care without transplantation. Randomized data on the approach to pretransplant cardiac evaluation are lacking.”

The need for more data led the authors of the AHA scientific statement to recommend “more comparative trials of alternative screening strategies for CAD among potential transplant candidates as an important priority for advancing the evidence basis for pretransplant evaluation and care.”

In the meantime, Dr. Lentine indicated that clinicians should be aware of current strategies for CV risk assessment specific to liver transplant candidates. Although she cited data suggesting CAD mortality after transplant can exceed 50% in groups with CAD established before transplant, “several cardiopulmonary problems are distinctly common among or unique to liver transplant candidates and pose increased risk for adverse outcomes, including pulmonary hypertension and the hepatopulmonary syndrome.”

■ Drs. Albeldawi and Lentine reported no conflicts of interest.

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY MAY 2013 2013

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From the Literature

Food Consumption Prior to Testing May Alter Results of Transient Elastography Experts Recommend Fasting for at Least Two Hours Before Testing for Liver Stiffness

BY CHRISTINA FRANGOU

to errors in clinical management,” concluded authors Umberto Arena, MD, Monica Lupsor Platon, MD, and their colleagues from the Università degli Studi di Firenze/Azienda Ospedaliero Universitaria Careggi, Firenze, Italy.

Authors of a new study have reported that measurements of liver stiffness vary significantly in the two hours after consumption of a meal, which can lead to overestimates of tissue fibrosis by transient elastograInvestigators found that liver stiffness phy (Arena U et al. Hepatologyy 2013 Feb 27. values collected within two hours [Epub ahead of print]). following consumption of a meal had “Even a minor overestimation of 3 to 4 kPa a lower probability of accurately [kilopascals] may have detecting fibrosis stage. a significant effect on the interpretation of this noninvasive method [of measurement], especially for the For the study, researchers meaearly stages of fibrosis, thus leading sured liver stiffness in 125 patients

(20-78 years of age) with chronic hepatitis C virus (HCV) infection using transient elastography (TE) following an overnight fast, and at 15, 30, 45, 60 and 120 minutes after consumption of a standardized liquid meal. The cohort included 40 patients with cirrhosis, 50 with mild or no fibrosis and 35 with significant or advanced fibrosis. Among the patients with cirrhosis, 27 were classified as Child-Turcotte-Pugh (CTP) class A and 13 as CTP class B. Esophageal varices were observed in 20 cases.

Liver stiffness increased within 15 to 45 minutes of meal consumption due to increased blood flow to the liver, and then returned to baseline values by the 120-minute mark in all cases. Patients with more advanced

fibrosis, especially those with cirrhosis, had significantly greater liver stiffness compared with patients with a lower fibrosis stage at the same time points. These patients also had a greater overall change in liver stiffness, although the percentage change was significantly greater among those with less severe fibrosis.

Investigators found that liver stiffness values collected within two hours following consumption of a meal had a lower probability of accurately detecting fibrosis stage, CTP class or esophageal varices compared with liver stiffness values at baseline. As a result of their research, the authors recommended that patients with chronic HCV infection should observe see Liver Stiffness, page 50

Drug-Induced Liver Injury in Elderly Patients Differs From Younger Patients

BY MONICA J. SMITH LAS VEGAS—Drug-induced liver injury (DILI) occurs in the elderly just as it does in younger populations, but the causes, clinical characteristics and outcomes differ, according to a recent report.

“We know anecdotally that DILI is seen in individuals who are older. … However, data are quite limited in terms of the nature of DILI in the elderly patient population, which may behave differently because of comorbidities and polypharmacy, as well as physiologic aging,” said study author Naga Chalasani, MD, chief, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis.

“The aim of our study was to compare the causative agents, clinical features and outcomes of DILI in the elderly with those of the nonelderly enrolled in the DILIN [Drug-Induced Liver Injury Network] prospective study,” Dr. Chalasani said.

The study included patients who had adjudication and those with a causality score of no more than 3, indicating definite, highly likely or probable causality.

Patients were considered elderly if they were aged 65 years or older. Of the 705 patients in the study cohort, 17% were elderly and 83% were nonelderly. A standard statistical analysis was made between the two populations. With the exception of age, other characteristics, such as gender and body mass index, were comparable.

“There were important differences in the implicated agents,” Dr. Chalasani reported. “Elderly patients were more likely to have DILI due to a single prescription agent, and less likely to have DILI due to CAM [complementary and alternative medicines]. As far as

‘Antimicrobials and lipid-lowering agents were more likely to cause DILI in the elderly, whereas CNS agents, NSAIDs and CAM [complementary and alternative medicines] were more likely to cause it in younger people.’

—Naga Chalasani, MD

individuall classes [of drugs], ant ntim tim imiic icro icro robi bial als ls an and d lipi pid iddlowering agents were more likely to cause DILI in the elderly, whereas CNS [central nervous system] agents, NSAIDs [nonsteroidal anti-inflammatory drugs] and CAM were more likely to cause it in younger people.”

The pattern of liver injury, too, was different. The elderly had more cholestatic DILI and lower alanine aminotransferase (ALT) levels than their younger counterparts. However, recovery time was similar for both groups.

“For example, [duration] from peak to normalization of ALT, or peak to bilirubin of less than 2.5 were not different,” Dr. Chalasani said.

There was a higher overall mortality in the elderly patients, but liver-related mortality did not appear to be different between the two groups. Chronic DILI was less common in elderly patients, “and this was a surprise

give gi ive ven n th that they have more cholestatic DILI,” Dr. Chalasani noted.

Researchers concluded that DILI in the elderly population has different causative agents, clinical characteristics and outcomes from the nonelderly population.

“It has long been believed that older age is a risk factor for developing DILI and that DILI is more severe in the elderly,” said Mitchell L. Shiffman, MD, a hepatologist at the Liver Institute of Virginia, Bon Secours Richmond Health System, in Richmond. “The data presented by Dr. Chalasani and the multicenter, National Institutes of Health–sponsored DILIN [Drug-Induced Liver Injury Network] group, have clearly confirmed these previous observations.”

The study was presented at the annual meeting of the American College of Gastroenterology.

■

H E PAT O L O G Y I N F O C U S

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

NAFLD continued from page 1

patients without evidence of cirrhosis.

“NAFLD-[related] HCC is increasing over time and it is independently associated with HCC without cirrhosis,” said senior investigator of the study, Jamal A. Ibdah, MD, PhD, professor of medicine and director, Division of Gastroenterology and Hepatology, University of Missouri School of Medicine, Columbia.

“Our data potentially suggest a unique underlying pathophysiology for development of HCC in noncirrhotic NAFLD.” The researchers used the Surveillance, Epidemiology, and End Results (SEER) database to examine the association of HCC with cirrhotic and noncirrhotic NAFLD. SEER contains 18 cancer registries, including HCC, and covers 28% of the U.S. population. Researchers analyzed data spanning 1993 to 2007, including individuals aged 65 years and older who were diagnosed with histologically confirmed HCC without multiple risk factors. A 5% sample of Medicare beneficiaries residing in the SEER geographical areas comprised the control group.

Researchers identified 17,895 HCC cases that met the study criteria. Overall, infection was the most common cause of HCC (44%), followed by alcoholic disease (19%) and NAFLD (16%), with other causes accounting for the remainder (21%).

“NAFLD was the third most common risk factor for HCC after infection and alcohol etiologies,” reported Rubayat Rahman, MD, MPH, a fellow in the Division of Gastroenterology and Hepatology at the University of Missouri, Columbia, who presented the study at The Liver Meeting of the American Association for the Study of Liver Dis-

18% of those had steatosis only. Among patients with NAFLD-related HCC, those without cirrhosis were more likely to have early stage I/II HCC (62% vs. 44%) and favorable grade I/II tumors (76% vs.

56%) compared with those with cirrhosis.

“Noncirrhotic NAFLD-[related] HCC cases have a better prognosis than cirrhotic NAFLD HCC cases,” Dr. Rahman noted.

The researchers also identified a dramatic increase in NAFLD-associated HCC without cirrhosis.

“Over time, NAFLD-[related] HCC without cirrhosis is proportionately increasing more than NAFLD-[related] HCC with cirrhosis,” Dr. Ibdah said.

Patients who had NAFLD-associated HCC without cirrhosis were more likely to be obese and to have diabetes mellitus and dyslipidemia (Table).

“This study is alarming,” said Guadalupe Garcia-Tsao, MD, professor of medicine, Yale School of Medicine, New Haven, and chief of the Section of Digestive Diseases at the VA Connecticut Healthcare System, West Haven, Conn.

cirrhosis, but we are very likely to see more liver cancer,” said Dr. Garcia-Tsao, who was not involved with the study.

NASH and Coffee Consumption In another study presented at The Liver Meeting, researchers showed that increased coffee consumption in patients with nonalcoholic steatohepatitis (NASH) was associated with a decreased risk for advanced fibrosis (defined as stage >2) among individuals with a low level of insulin resistance (defined as homeostatic model assessment of insulin resistance [HOMA-IR] <4). The researchers conducted this study because previous studies had identified positive effects of coffee consumption in NAFLD patients with type 2 diabetes and hepatic fibrosis. The investigators hypothesized that the effect of coffee might be dependent upon the severity of NAFLD and that the association may be influenced by an individual’s degree of insulin resistance.

The investigators used cross-sectional data from 782 patients who were prospec-

‘[NAFLD] is currently one of the most common causes of chronic liver disease and is strongly associated with the obesity epidemic. If the obesity epidemic increases, we are not only going to see more chronic liver disease and more cirrhosis, but we are very likely to see more liver cancer.’

—Guadalupe Garcia-Tsao, MD

‘NAFLD-[related] HCC is increasing over time and it is independently

Table. Characteristics of Patients With NAFLD-Related HCC With and Without Cirrhosis

associated with HCC

Without Cirrhosis, %

With Cirrhosis, %

P Value

without cirrhosis. Our data

Obesity (BMI ≥30)

89.7

79.8

<0.01

potentially suggest a unique

Diabetes mellitus

82.7

71.0

<0.01

underlying pathophysiology

Dyslipidemia

71.0

47.2

<0.01

for development of HCC in

Hypertension

62.1

63.4

NS

noncirrhotic NAFLD.’

BMI, body mass index (kg/m2); HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease

—Jamal A. Ibdah, MD, PhD eases (AASLD). “However, in U.S. Asian and Pacific Islanders, it was the second most common risk factor after infection.”

Surprisingly, 36% of patients who developed HCC as a result of fatty liver disease had no evidence of cirrhosis:

questionnaires recorded coffee consumption in terms of average cups per day, up to five cups per day. No distinction was made between caffeinated and decaffeinated coffee.

Overall, 79% of patients had definite or probable NASH, and of these, 75% had fibrosis that was stage 2 or lower.

Cirrhosis was present in 8% of patients.

The median HOMA-IR score was 4.3, and 24% of individuals had diabetes and 56% had hyperlipidemia. Coffee was consumed daily by 71% of subjects, with 28% drinking at least two cups per day and 11% drinking three or more cups per day.

The investigators found a significant inverse association between coffee consumption and the severity of fibrosis according to HOMA-IR scores (P=0.001).

P A multivariate analysis found a significant inverse association between coffee consumption and advanced fibrosis among NASH patients with lower HOMA-IR scores (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.460.88; P=0.007).

P

“[NAFLD] is currently one of the most common causes of chronic liver disease and is strongly associated with the obesity epidemic. If the obesity epidemic increases, we are not only going to see more chronic liver disease and more

tively enrolled in The Clinical Research Network of NASH from 2004 to 2008.

Patients included in the study were aged 18 years or older and had data available on NAFLD, liver histology and coffee consumption. Self-reported dietary

“Increased coffee intake was associated with a significantly decreased risk for advanced fibrosis among individuals with lower HOMA-IR [<4], but there was no significant association among individuals with higher HOMA-IR [≥4],” said Kiran Bambha, MD, assistant professor of medicine in the Division of Gastroenterology at the University of Colorado School of Medicine, Aurora, who presented the study at The Liver Meeting.

Dr. Bambha noted that coffee has hundreds of components besides caffeine, including phenolic compounds such as chlorogenic acids, which have been shown to have an effect on insulin and glucose response, as well as having antioxidant properties.

“What is needed are longitudinal, well-designed studies to further delve into what associations may exist between

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY MAY 2013 2013

coffee and hepatic fibrosis, and whether or not coffee may be a useful adjunct therapy for patients with fatty liver disease,” Dr. Bambha said.

Dr. Garcia-Tsao agreed: “We need longitudinal prospective studies that confirm these preliminary findings, before we can openly recommend coffee to our NAFLD patients.”

NASH and Intestinal Microbiota

(P=0.006).

P Adjusting for body mass index (BMI) and percentage of fat intake, a significant association between the presence of NASH and lower percentage of Bacteroidetess was seen (P P=0.002). Other microbes were not associated with NASH after controlling for BMI and percentage of fat intake. Additionally, an inverse correlation between the percentage of Bacteroidetess and HOMA-IR was found.

“Patients with NASH seem to have a

lower percentage of Bacteroidetes compared with healthy controls and patients with simple steatosis,” Dr. Mouzaki said.

“There seems to be a BMI- and percentage fat intake–independent association between the percentage of Bacteroidetes in the stool and the presence of NASH, and an inverse correlation between the percentage of Bacteroidetes and insulin resistance.”

If further studies can confirm this

15

study’s findings, controlling the intestinal microbiota might be a new treatment strategy.

“The ultimate goal is to see whether we can detect differences [in intestinal microbiota] that can then be therapeutic targets for NAFLD,” Dr. Mouzaki said.

■ Drs. Ibdah, Rahman, Garcia-Tsao, Bambha and Mouzaki have no relevant disclosures.

In a third study presented at The Liver Meeting, Marialena Mouzaki, MD, MSc, of the Department of Pediatrics, Division of Gastroenterology, Hospital for Sick Children, University of Toronto, Canada, and her colleagues found that the intestinal microbiota of patients with NASH differed from those of patients with simple steatosis and healthy controls, after controlling for factors such as obesity and diet. Dr. Mouzaki said it was the first study to identify a difference.

‘The ultimate goal is to see whether we can detect differences [in intestinal microbiota] that can then be therapeutic targets for NAFLD.’ —Marialena Mouzaki, MD, MSc

The study recruited 50 individuals older than 18 years of age, 22 with NASH, 11 with simple steatosis and 17 healthy controls.

“The healthy controls were adults who were undergoing assessment for hepatic donation for transplantation and had a biopsy as part of the workup or at the time of donation,” Dr. Mouzaki noted.

Patients were excluded if they were heavy alcohol drinkers, had chronic gastrointestinal conditions, had been taking intestinal microbiota–altering medications within six months, were currently taking vitamin E or C, or were pregnant/lactating.

Patients provided stool samples, and the investigators measured fecal levels of Bifidobacteria, Bacteroidetes, Clostridium coccoides, Clostridium leptum, Escherichia coli, total bacteria and Archaea. Patients also completed seven-day food diaries and seven-day activity logs, and had blood drawn for metabolic parameters.

The researchers found a significantly lower percentage of Bacteroidetess in patients with NASH than in patients with simple steatosis and healthy controls

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS “After an episode of [overt HE], prophylactic therapy with lactulose or rifaximin is recommended for an indefinite period of time or until liver transplantation.”

—Clinics in Liver Disease, February 20121 73% of recurrences among lactulose patients result in hospitalization 2 Xifaxan 550 mg reduces the risk of HE-related hospitalizations by 50%3†‡ The most common adverse reactions (≥12% incidence) in clinical trials with Xifaxan 550 mg were peripheral edema, nausea, dizziness, and fatigue.

Prescribe. Protect. Repeat.

*HE=hepatic encephalopathy. † Over a 6-month period; P=0.0129 vs placebo.3 ‡ HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.3

Important Safety Information About XIFAXAN 550 mg XIFAXAN® (rifaximin) 550 mg tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFA X AN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother.

The most common adverse reactions occurring in ≥10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%).

Xifaxan 550 mg is not available for sale outside the U.S. Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see Brief Summary on reverse.

References: 1. Khungar V, Poordad F. Management of overt hepatic encephalopathy. Clin Liver Dis. 2012;16(1):73-89. 2. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):10121017. 3. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc; 2011.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74-1

www.Xifaxan550.com

16

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

From the Literature

Retreatment of Patients With Chronic HCV Infection With Interferon Alone May Increase Mortality

BY GEORGE OCHOA Retreatment of patients with chronic hepatitis C virus (HCV) infection with interferon (IFN) alone does not appear to provide significant clinical benefit and may even increase all-cause mortality, according to researchers of a Cochrane review (Koretz RL et

The following is a brief summary; see complete Prescribing Information at www.Xifaxan550.com.

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

al. Cochrane Database Syst Rev 2013;1:CD003617). Surrogate outcomes improved, however, especially sustained viral response (SVR) and markers of inflammation, despite the poor clinical outcome. The researchers concluded that such surrogates “are not adequate outcomes to use for treatment.”

had a mean age of 56.26 (range: 21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).

Table 1: Adverse Reactions Occurring in ≥ 5% of Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo

Hepatic Encephalopathy XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.

In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed.

XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores > 25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction [see Warnings and Precautions (5.4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

CONTRAINDICATIONS Hypersensitivity XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis [see Adverse Reactions (6.2)].

WARNINGS AND PRECAUTIONS Travelers’ Diarrhea Not Caused by Escherichia coli XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered.

XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug Resistant Bacteria Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Severe (Child-Pugh C) Hepatic Impairment There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

ADVERSE REACTIONS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hepatic Encephalopathy The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280). The population studied

Number (%) of Patients

MedDRA Preferred Term Edema peripheral Nausea Dizziness Fatigue Ascites Muscle spasms Pruritus Abdominal pain Abdominal distension Anemia Cough Depression Insomnia Nasopharyngitis Abdominal pain upper Arthralgia Back pain Constipation Dyspnea Pyrexia Rash

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

21 (15%) 20 (14%) 18 (13%) 17 (12%) 16 (11%) 13 (9%) 13 (9%) 12 (9%) 11 (8%) 11 (8%) 10 (7%) 10 (7%) 10 (7%) 10 (7%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 7 (5%)

13 (8%) 21 (13%) 13 (8%) 18 (11%) 15 (9%) 11 (7%) 10 (6%) 13 (8%) 12 (8%) 6 (4%) 11 (7%) 8 (5%) 11 (7%) 10 (6%) 8 (5%) 4 (3%) 10 (6%) 10 (6%) 7 (4%) 5 (3%) 6 (4%)

The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure.

Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain Investigations: Weight increased Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Psychiatric Disorders: Confusional state Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis Vascular Disorders: Hypotension

Postmarketing Experience The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Infections and Infestations Cases of C. difficile-associated colitis have been reported [see Warnings and Precautions (5.2)].

General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

DRUG INTERACTIONS In vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use.

“If you have an invalid outcome, that’s the most pressing concern,” said lead researcher Ronald L. Koretz, MD, emeritus professor of clinical medicine, University of California, Los Angeles. “Since the currently employed outcomes are not valid, we’re treating people with no knowledge of whether we’re doing any good,” he said.

An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.

An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium.

The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients, based upon plasma AUC comparisons.

Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.

Nursing Mothers It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established. The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age.

Geriatric Use Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.

Hepatic Impairment Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC␶) of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally.

Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)].

Manufactured for Salix Pharmaceuticals, Inc., Raleigh, NC 27615, under license from Alfa Wassermann S.p.A. XIFAXAN® is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A. Copyright © Salix Pharmaceuticals, Inc.

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74

Another message of the review, Dr. Koretz noted, is the increased risk for mortality associated with IFN treatment. “Whether you take it alone or with other drugs, there may be an increased risk for dying.”

In the Cochrane review, researchers studied seven randomized trials (N=1,976) comparing IFN monotherapy with placebo or no treatment in patients with chronic HCV infection who were nonresponders and relapsers to previous IFN treatments. Two (n=1,676) of the seven trials—HALTC (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) and EPIC3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis)— were large trials at low risk for bias; the other trials (n=300) had a high risk for bias. When all three trials providing mortality data were considered, all-cause mortality was not significantly different, but when only the two trials at low risk for bias were combined, all-cause mortality was significantly higher among recipients of pegylated IFN (78 of 828 [9.4%] vs. 57 of 848 [6.7%]; relative risk [RR], 1.41; 95% confidence interval [CI], 1.02-1.96).

Variceal bleeding occurred less often in patients treated with IFN (four of 843 [0.5%] vs. 18 of 867 [2.1%]; RR, 0.24; 95% CI, 0.09-0.67), but no differences were found with regard to development of ascites, encephalopathy, hepatocellular carcinoma and

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

inhibitors, along with ribavirin.”

Dr. Koretz acknowledged the new IFN-free treatments in the pipeline, but noted that, in the meantime, the potential mortality risk associated with IFN should be addressed.

“People are talking about non-IFN regimens, but right now we’re using IFN. We need to inform patients,” he said.

“This should be part of informed consent,” Dr. Koretz continued.

“Henceforth patients may be treated with IFN, but they should be told there

may be a risk for increased mortality.”

Dr. Koretz noted that the FDA had not added a black box warning regarding the risk for increased mortality from IFN “even though the HALTC trial, a major study, reported this increase in mortality two years ago.

“Even so, treating physicians should alert patients to whom they are offering therapy,” he said.

The FDA did not respond to a request for comment.

“Even with a non-IFN regimen, the failure of the surrogate

17

outcome—SVR—to validate, is still an issue,” said Dr. Koretz. Nevertheless, SVR is still being used, he said.

“SVR has become hepatologic dogma. One of my concerns is that some opinion leaders have potential conflicts of interest with industry, such as research support or positions on speakers’ bureaus.”

■ Dr. Koretz reported no relevant conflicts of interest. Dr. Chung reported participating in research trials for Genentech, Gilead, MassBiologics and Merck & Co.

CO2 instead of room air for GI endoscopy?

It’s about comfort. nfi

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liver transplantation. Adverse events (AEs) were more common in patients treated with IFN. Patients receiving IFN were more likely to achieve SVR (20 of 557 [3.6%] vs. one of 579 [0.2%]; RR, 15.38; 95% CI, 2.9380.71) and to have improvements in markers of inflammation.

“In the trials with low risk for bias,” Dr. Koretz observed, “there was a significant difference in mortality, with the recipients of the pegylated interferon having a significantly higher death rate. Although this may be a type 1 error, it is the only data we currently have. It’s a troubling observation.”

Raymond T. Chung, MD, vice chief, gastrointestinal unit and medical director of the Liver Transplant Program at Massachusetts General Hospital’s Digestive Healthcare Center in Boston, who was not involved in the study, pointed out that the concern about IFN may soon be obsolete.

“Although this is a well-done study on an important topic, the topic may soon be superseded by forthcoming advances in antiviral regimens that will address, among other populations, prior IFN nonresponders,” he said. “These regimens will include IFN-sparing combinations of potent direct antiviral classes.”

Dr. Chung added that some of the IFN-free treatment regimens may include “nucleotide polymerase inhibitors, NS5A inhibitors, protease inhibitors and non-nucleoside polymerase

de

Better for your patients Better for you s CO2 insufflation during ERCP may “significantly reduce[] postprocedural abdominal pain.” 1 s #/2 is absorbed 150 times faster than the nitrogen in air, and is promptly eliminated via the lungs.2 s CO2 insufflation “reduces pain and is safe to use in colonoscopy in sedated patients”. 3 Indications for Use: The CO2EFFICIENT Endoscopic Insufflator is designed to use CO2 as a distention media in the gastrointestinal tract when used in conjunction with a gastrointestinal endoscope.

For additional product information please visit www.bdigastro.com

Contraindications for Use: The CO2EFFICIENT ENDOSCOPIC INSUFFLATOR™ should be used only for an endoscopic procedure when insufflation of the gastrointestinal tract is necessary to support navigation of the endoscope and perform any evaluation procedures through the endoscope, and should therefore not be used for any other treatments. It should only be used under the direct guidance of a physician experienced in Gastrointestinal Endoscopy procedures. This device is contraindicated for hysteroscopic or laparoscopic insufflation, i.e., it must not be used for intrauterine distension. This device is contraindicated for CT Colonography.

For questions or instructions for use, please contact Bracco Diagnostics Professional Services Department at 800-257-5181, option 2.

References: 107 College Road East P.O. Box 5225 Princeton, NJ 08540 Ph: 609-514-2200 Toll Free: 1-800-631-5245 Fax: 609-514-2446

1. Bretthauer M, Seip B, et al. Carbon dioxide insufflation for more comfortable endoscopic retrograde cholangiopancreatography: a randomized, controlled, double-blind trial. Endoscopy 2007; 39:58-64.

2. Grant DS, Bartram CI, Heron CW, A preliminary study of the possible benefits of using carbon dioxide insufflation during double-contrast barium enema. The British Journal of Radiology 1986; 59:190-191.

3. Bretthauer M, Lynge AB, et al. Carbon dioxide insufflation in colonoscopy: Safe and effective in sedated patients.

Endoscopy 2005; 37:706-709.

© 2012 Bracco Diagnostics Inc. All rights reserved.

18

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

HCV Screening continued from page 1

on HCV screening to support one-time screening for all baby boomers.

Hepatologists insist that a strong recommendation from the task force will save both lives and dollars in the long run.

“If we can get a single, coordinated effort to get all baby boomers screened, that is going to be best for our patients,” said Neeral Shah, MD, a hepatologist and assistant professor of internal medicine at the University of Virginia School of Medicine in Charlottesville. “Without such a recommendation, we’re going to continue to miss the 800,000 people who do not know they have hepatitis C.

screening for that age cohort.

In a statement explaining the decision, task force member Kirsten BibbinsDomingo, MD, PhD, MAS, associate professor of medicine, epidemiology and biostatistics at the University of California, San Francisco, said: “Based on what we know today, the task force concluded that screening provides substantial benefits for people at high risk. We also found that screening people from the baby-boom

generation also provides real, although smaller, benefits. People at high risk have about a 50% chance of being infected with hepatitis C, whereas people born between 1945 and 1965 have a 3% to 4% chance of being infected.”

Hepatologists Lobby for Change For specialists in hepatology and infectious disease, the USPSTF decision comes up short.

‘If we can get a single, coordinated effort to get all baby boomers screened, that is going to be best for our patients. Without such a recommendation, we’re going

mobile!

to continue to miss the 800,000 people who do not know they have hepatitis C.’ —Neeral Shah, MD

“There is a British term, ‘penny wise, pound foolish,’ ” he added. “If we try to save our money now by not screening the population to find these people with silent hepatitis C, then we’ll be dealing with the enormous costs of end-stage liver disease and transplant down the line.”

gastroendonews.com

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Conflicting Recommendations In August, the Centers for Disease Control and Prevention (CDC) recommended a one-time screening for all Americans born between 1945 and 1965.

According to the CDC report, 75% of HCV-infected individuals in the United States were born during those years, but the overwhelming majority—as many as 75%—are unaware of their HCV [hepatitis C virus] status.

The CDC said that screening baby boomers could lead to the detection of more than 800,000 HCV infections, and avert cases of advanced liver disease and as many as 120,000 deaths.

But the CDC’s recommendation received a lukewarm response from the USPSTF. In its draft opinion, the task force said screening should be offered to adults at high risk, such as those with a history of IV drug use and those who received blood transfusions before 1992.

For baby boomers, the task force said clinicians may “consider offering” HCV

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Douglas R. LaBrecque, MD, professor and director of Liver Service, Department of Internal Medicine, University of Iowa, University Heights, argued that, by definition, all baby boomers in the United States are high-risk.

“One in 30 baby boomers is going to be positive. That’s pretty high risk,” he said. He added that many cases of hepatitis C will be missed if screening efforts target only IV drug users or people who

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY MAY 2013 2013

received blood transfusions before 1992.

“Look at it this way: Most patients don’t even know if they have risk factors or, if they do, they don’t tend to admit that to their family doctor. So the best risk factor we can identify for hepatitis C is the [baby boomer] age cohort,” Dr. LaBrecque said. “By screening this cohort, we’ll identify three-fourths of those patients. If we can identify threefourths of patients, we’re going to make

‘Look at it this way: Most patients don’t even know if they have risk factors or, if they do, they don’t tend to admit that to their family doctor. So the best risk factor we can identify for hepatitis C is that [baby boomer] age cohort.’

—Douglas R. LaBrecque, MD a huge step forward in trying to prevent complications of [liver] disease and in reducing the cost of treating the disease.

The expense of treating someone with advanced liver disease—much less transplanting them, is huge compared

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with the cost of treating the virus in the first place.”

Dr. LaBrecque also noted that treatments for HCV infection have become so successful that 70% to 80% of infected patients can have the disease eliminated if caught early. That figure is expected to rise to 90% within the next two years.

According to Dr. Shah, if the panel adopted a recommendation for see HCV Screening, page 21

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Volume 64, Number 1 • January 2013

ACG 2012

IBS No Longer Only Functional Disorder

Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search

BY DAVID WILD

BY CHRISTINA FRANGOU LAS VEGAS—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see IBS, page 8

Mesalamine Elicits Response in IBS

BY MONICA J. SMITH LAS VEGAS—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9

If they haven’t already, fellows and residents should add one more resolution to their New Year’s list: Start the job search.

The earlier that trainees begin the search, the better, experts say. Many recommend that residents and fellows start the process 18 months before they are due to finish training.

With recruiting season kicking into high gear over the next few months, Gastroenterology & Endoscopy Newss summarized some practical tips for finding a job in academic medicine or private practice, as outlined by two gastroenterologists with experience in each area. see Job Search, page 25

Experts’ Picks

I N S I D E

Best of the American College e Of Gastroenterology: Part 2

MDs and DOs Plan Unified Accreditation System For Graduate Medical Education ............... page 5

EXPERT REVIEW: Sexual Misconduct by Professionals: A New Model of Understanding

COMPILED AND WRITTEN BY DAVID WILD Gastroenterology & Endoscopy Newss asked several experts to select their favvorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scien ntific Meeting.

Inside is a collection of their selections and comments that reflect the varied interests of the experts who we interviewed. (Part 1 of this series appeared in the Decemberr 2012 issue of Gastroenterology & Endoscopy News.) see Best of ACG, page 14

BY GREGORY E. SKIPPER, MD, AND STEPHEN SCHENTHAL, MD..................... page 29

EXPERT REVIEW: Safeguarding Yourself Against Allegations Of Sexual Abuse or Patient Impropriety

BY HARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD .................................................................. page 33

PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37

The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11

We are proud to be the best-read gastroenterology publication in the marketplace, and we look forward to continuing to be your #1 source for gastroenterology news in decades to come.

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HCV Screening continued from page 19

widespread screening, Medicare and most private health insurers would be required to pay for the tests under the 2010 Affordable Care Act. But without that recommendation from the task force, and the consequent backing of insurance companies and Medicare, screening of the baby boomer generation on a mass scale is unlikely to happen.

“Insurance companies are not likely to cover the test when there are differing recommendations,” he said.

for Liver Diseases, Scripps Clinic, La Jolla, Calif.

“It really must be adapted as task force guidelines in order for primary care physicians to be mandated to order the tests. That has not happened with the current C-level recommendation [from the task force] and is not likely to happen until it is changed to a B- or A-level recommendation.”

In March, Dr. Shah and other members of the American Association for the

them to care, would save more than 120,000 lives,” said the IDSA. The IDSA warned that the task force’s current “tepid recommendation” will influence medical practice and could be used by private and public insurers as a reason to limit coverage and access to screening services.

Hepatologists do not expect any uptick in diagnosis rates without a strong recommendation from the task force.

Marlyn Mayo, MD, a liver disease

whose disease has not progressed, said Fasiha Kanwal, MD, MSHS, associate professor of medicine, Baylor College of Medicine in Houston, and her colleagues in a recent article published in the March editions of Gastroenterology and Clinical Gastroenterology and Hepatology (Gastroenterology 2013;144:478481; Clin Gastroenterol Hepatol 2013;11:200-203).

New HCV treatments are more likely to be simpler, better tolerated and more

The Infectious Diseases Society of America (IDSA) is calling upon the USPSTF to revise its final recommendation and align with the CDC. Broad screening, ‘which is critical to identifying those who are infected, and linking them to care, would save more than 120,000 lives,’ said the IDSA.

Experts say that now is the time to act. HCV cure rates have risen from about 50% to closer to 80% with the new HCV protease inhibitors and are expected to improve again as more therapies, including interferon-free therapies, are approved over the next two years.

A stronger recommendation from the task force also would help raise public awareness about hepatitis C. The lack of awareness has proved a major hurdle in hepatitis treatment over the past two decades, and many people do not know their risks and primary care physicians are not screening patients for hepatitis C, Dr. LaBrecque said.

“For some reason, HCV doesn’t seem to be on the radar of most primary care providers, whether they are family doctors, internal medicine, or obstetrics and gynecology. Patients are not getting screened for HCV. They’re getting their mammograms [and] their colonoscopies but liver disease doesn’t register even though the fastest rising cancer in the U.S. is liver cancer and that’s related to viral hepatitis.”

Gastroenterologists and hepatologists do not see enough of this patient population to influence screening rates, “except to screen the few sent for CRC [colorectal cancer] screening—a fraction,” said Paul Pockros, MD, director of the Center

Study of Liver Diseases’ Public Policy Committee traveled to Washington, D.C., to ask members of Congress to support a policy of one-time screening for all baby boomers. They met with representatives in the House and the Senate and asked them to send a letter to the task force urging them to reconsider the recommendation.

“Before the USPSTF finalizes this draft, we were hoping to garner support to help educate them about the danger of this recommendation, as the current recommendation would allow insurance companies to refuse to cover this $30 test, and pass the cost on to the patient.

It will slow the search to find those 800,000 people who do not know they have hepatitis C.” The Infectious Diseases Society of America (IDSA) also is calling upon the USPSTF to revise its final recommendation and align with the CDC. Broad screening, “which is critical to identifying those who are infected, and linking

specialist at UT Southwestern Medical Center in Dallas, said she has not yet seen a single patient whose HCV was discovered due to screening as a baby boomer.

“When I do ask patients how their HCV was discovered, they still report either riskbased screening or incidentally discovered, elevated transaminases as the reason.”

She added “as there has been, and continues to be, a steady stream of referrals for newly identified hepatitis C, we’ve barely uncovered the tip of the iceberg.”

Early Diagnosis Crucial For Success Experts said that now is the time to act. Cure rates have risen from about 50% to closer to 80% with the new HCV protease inhibitors and are expected to improve again as more therapies, including interferon-free therapies, are approved over the next two years.

These new therapies have a much greater chance of success in patients

efficacious than current treatments but the safety and effectiveness will remain “relatively low” in people with cirrhosis or older patients with multiple comorbidities.

Dr. Kanwal said that one-time testing of all baby boomers would “accelerate the identification of most HCV-infected persons before progression to cirrhosis.

“Early diagnosis is crucial for infected persons to benefit from new HCV treatment and to decrease the burden of HCV.” If the experience with HIV is any example, the task force won’t be making any changes in the near future, said Dr. Pockros. The task force just recommended HIV testing last winter, an announcement made 15 years after HIV protease inhibitors changed the course of HIV infection.

“It took that long to collect enough ‘evidence-based medicine’ in order to cement the recommendation,” he said.

“How long will that take for HCV?” ■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

From the Literature

Triple Therapy Including a Protease Inhibitor Achieves Higher SVR Rates for Genotype 1 HCV Infection, Study Confirms

BY CHRISTINA FRANGOU Patients with the most prevalent type of hepatitis C virus (HCV) infection have a substantially higher likelihood of achieving a sustained virologic response (SVR) with a triple therapy that includes an HCV protease

inhibitor, a recent report confirmed.

The findings validate triple therapy as the first-line treatment for genotype 1 hepatitis C (Chou R et al. Ann Intern Med 158:114-123).

Triple therapy quickly became the general practice in urban centers throughout the United States after the drugs were approved in 2011, and

the regimen has been adopted slowly as standard treatment throughout the rest of the country, said Paul Pockros, MD, director, Center for Liver Diseases, Scripps Clinic, San Diego.

“I think [triple therapy] is widely adopted now,” said Dr. Pockros, who was not involved in the study.

In the report, lead author Roger

Investigators reported that no trial in the past 70 years has focused on long-term clinical outcomes after treatment. Instead, studies rely on SVR as the primary outcome measure.

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Chou, MD, MPH, assistant professor of medicine, Division of General Internal Medicine and Geriatrics at Oregon Health & Science University, in Portland, and his colleagues assessed 379 studies identified by searching multiple databases dating between 1947 and August 2012. The studies included all randomized trials of antiviral treatments and cohort studies examining associations between SVR after therapy.

Their analysis revealed that, for HCV genotype 1 infection, “fair-quality trials” demonstrated that triple therapy with pegylated interferon (PEGIFN), ribavirin and either boceprevir or telaprevir increases the likelihood for achieving SVR by between 22% and 31% compared with dual therapy not including a protease inhibitor.

Triple therapy for HCV genotype 1 infection also was associated with a shorter duration of treatment, “an important consideration given the high frequency of adverse effects associated with interferon-based therapy,” the authors said.

Their findings also confirm the well-documented increase in adverse events (AEs) for triple-therapy regimens. Compared with dual therapy, triple therapy including boceprevir was associated with a greater risk for hematologic AEs and triple therapy including telaprevir was linked to higher rates of anemia and rash.

The authors said their findings have important implications

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY MAY 2013 2013

‘This has been an area of controversy in the field for a number of years. With the slow natural history of hepatitis C, it was difficult to demonstrate the benefits in accepted clinical outcomes.’

—Andrew J. Muir, MD, MHS

for treatment as well as screening because “screening benefits depend in part on the effectiveness of available treatments.”

Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Diseases at the University of Chicago Medicine, said that this study confirms previous studies and an FDA review.

“Triple therapy with a protease inhibitor is the current standard of care … this is currently what everyone does,” Dr. Jensen said.

Investigators reported that no trial in the past 70 years has focused on longterm clinical outcomes after treatment.

Instead, studies rely on SVR as the primary outcome measure. The authors said that it’s difficult to evaluate longterm clinical outcomes other than SVR because HCV infections develop over many years.

However, the authors said evidence suggested that SVR is associated with a lower risk for all-cause mortality. The strongest evidence comes from a cohort study published in 2011 that showed SVR was associated with a 30% to 50% reduction in mortality risk, after adjusting for confounders (Backus LI et al. Clin Gastroenterol Hepatol 2011;9:509-516). Dr. Chou and his colleagues said the study provides “strong evidence” that virologic and clinical outcomes are linked.

That may be the most important finding in the report, commented Andrew J. Muir, MD, MHS, clinical

director of hepatology, Department of Medicine at Duke University in Durham, N.C. “This has been an area of controversy in the field for a number of years. With the slow natural history of hepatitis C, it was difficult to demonstrate the benefits in accepted clinical outcomes. The lack of clear clinical benefit also kept some from accepting the value of hepatitis C treatment.”

In other findings, investigators reported that dual therapy with

H E PAT O L O G Y I N F O C U S

PEG-IFN alfa-2b was associated with a reduced rate of SVR by about 8% compared with PEG-IFN alfa-2a.

However, PEG-IFN alfa-2b was associated with a lower risk for serious AEs, “suggesting potential tradeoffs between benefits and harms,” said the authors.

For patients with HCV genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood for achieving SVR than was therapy for 24 weeks, and

23

lower doses of PEG-IFN alfa-2b were less effective than standard doses, according to evidence from two to four fair-quality trials.

Across all regimens, absolute SVR rates were lower in older patients, black patients, patients with more advanced fibrosis and patients with higher viral load, the researchers noted.

■ The study was supported by the Agency for Healthcare Research and Quality. The authors reported no relevant conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Statins Linked to Reduction in Mortality From Liver Cancer Study Highlights HCC Progression in Contrast to Previous Studies Focused on HCC Risk

BY CAROLINE HELWICK SAN FRANCISCO—Patients with hepatocellular carcinoma (HCC) who took statins had a 30% lower mortality rate than those who did not, in a study from the University of Texas MD Anderson Cancer Center, Houston, presented at the 2013 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

“Several observational studies have shown an inverse association between statin use and HCC incidence, but little is known as to whether statins can delay the progression of HCC. We investigated the association between statin use and the outcome of patients with HCC,” said lead investigator Young Kwang Chae, MD, MPH. The study involved 644 patients (mean age, 63 years) who underwent local and systemic therapy (82%) or surgical resection (18%) for HCC. Statin use, defined as use at the time of the initial clinic visit and for at least three months after, was reported by 10.7% of patients.

“We observed significant differences in overall survival [OS] between statin nonusers and users,” Dr. Chae reported.

“A 30% mortality reduction was observed in statin users versus nonusers, and this significant association was also observed in patients who received systemic and local therapy.”

Median OS for all patients in the study was 19.2 months. The median OS for statin users versus nonusers was 22.2 and 18 months, respectively (P=0.04).

P For HCC patients without cirrhosis, median OS was 31.7 months versus 21.8 months in statin users versus nonusers, respectively

(P=0.06), P with a reduction in mortality of 30%. However, the protective effect of statins was not seen in patients with cirrhosis, whose median OS was 17.5 months in statin users and 18.9 months in nonusers (P=0.8).

P According to Dr. Chae, the lack of effect of statins use in patients with cirrhosis is an issue of timing.

“Some patients die of cirrhosis before their HCC takes over. Also, patients with advanced disease, such as cirrhosis, do not have much time for the drug of interest to have any effect,” he said.

“Even after controlling for various clinical variables, including age, sex, race, staging, hepatitis B and C, cirrhosis, treatment, alcohol use and diabetes, statin use was still associated with favorable overall survival in

HCC patients,” he said.

Fu r t h e r m o re, although patients in the statin treatment group were older and more had cardiovascular disease, diabetes and other comorbidities, they actually lived longer, the researchers noted.

Dr. Chae pointed out that HCC is a very vascular disease, and preclinical evidence supports the antitumor activity of statins.

“Statins are known to have modulatory effect on the post-translational modification of oncogenic proteins,” he said. “They are also known to modulate angiogenesis processes as well.”

However, the findings are hypothesisgenerating only at this point, and should be validated in a prospective trial, he added.

William Grady, MD, the Roger C. Haggitt Endowed Chair in Gastroenterology and professor of medicine and chief of gastroenterology at the University of Washington Medical Center, in Seattle, commented on the findings.

“There has been an interest in the potential role of statins in tumor prevention in a variety of cancers for quite some time. This interest is a result of the common use of statins for the treatment of hyperlipidemia and because of the biological plausibility of these drugs as being anticancer therapies. Statins can affect the isoprenylation of a number of potential oncogenes, such as RhoB B and KRAS, and suppress their function,” said Dr. Grady, who also is a research scientist at the Fred Hutchinson Cancer Center, in Seattle.

“This study is unique in that most studies of statin use in cancer have focused on cancer risk rather than on cancer progression,” Dr. Grady noted (e.g., Singh S et al. Gastroenterologyy 2013;144:323-332; Tsan YT et al. J Clin Oncoll 2013;31:15141521). “The favorable association of statin use with survival in this group of patients with HCC is especially notable because many patients taking statins have comorbid conditions that would be predicted to worsen survival.”

Morris Sherman, MD, of Toronto General Hospital, Ontario, Canada, and chair of the Canadian Liver Foundation, was more cautious in his interpretation of the data.

“This study does not prove the point.

In any case, data presented in abstract form is insufficient to trigger a change in practice. A proper randomized controlled trial is necessary” to confirm the findings, he said.

■

Treatment With Statins Associated With Reduced Risk for Esophageal Cancer

BY TED BOSWORTH LAS VEGAS—A meta-analysis has linked statin therapy with a relatively large reduction in the risk for esophageal cancer. The risk reduction was particularly pronounced in patients with Barrett’s esophagus (BE). In this population, statin use was associated with a 40% lower rate of esophageal cancer after adjusting for major confounders, such as body mass index, use of proton pump inhibitors or use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Based on the degree of risk protection and the consistency of benefit, randomized trials may be a reasonable next step, particularly in those with BE, according to Siddharth Singh, MD, a

gastroenterologist in the Department of Gastroen- patients attending primary care practices were terology and Hepatology, Mayo Clinic, Rochester, identified. The data from the meta-analysis proMinn. Presenting these results at the annual meet- duced an adjusted odds ratio (OR) of 0.72 (95% ing of the American College of Gastroenterology, confidence interval [CI], 0.60-0.86) for esophageal Dr. Singh estimated that a statin trial of four to five cancer among statin users relative to those who years’ duration may be did not take a statin. Consufficient to demon- ‘Using data from observational studies, siderable heterogeneity strate protection from among the studies, which esophageal cancer in we are unable to estimate the effective employed different stratepatients with high-risk dose, the duration or the best time gies for estimating statin BE. exposure, led Dr. Singh to start statins in order to obtain From a systematic chemoprevention.’ and his co-investigators to search of Medline and conduct a more restricted —Siddharth Singh, MD analysis of the seven most other sources, 13 studies were included in rigorous and highest-qualan initial analysis, where 9,300 cases of esopha- ity studies. Again, statin therapy was associated geal cancer in a population base of 1.1 million see Statins, page 25

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Meta-Analysis Finds No Link Between Bisphosphonates and Esophageal Cancer Longer, Prospective Studies Needed To Clarify Previous Conflicting Reports

BY DAVID WILD LAS VEGAS—Bisphosphonate use does not increase the risk for esophageal cancer, according to results from a metaanalysis of eight large observational studies.

“As for now, there is no strong evidence that oral bisphosphonates increase the risk for esophageal cancer. For patients appropriately prescribed bisphosphonates, these medications should not be discontinued solely on the basis of cancer risk,” said lead investigator Saowanee Ngamruengphong, MD, a fellow in the Department of Gastroenterology at Mayo Clinic, Jacksonville, Fla. A number of studies have been conducted on the topic but have yielded conflicting results. To examine the possible link between the use of bisphosphonates and esophageal cancer, Dr. Ngamruengphong and her colleagues scoured several literature databases as well as conference abstracts published from 1950 onward, for controlled observational studies on the topic. They presented their findings at the American College of Gastroenterology Annual Scientific Meeting.

Dr. Ngamruengphong’s team identified four case–control studies and four

cohort studies, including data from 196,231 bisphosphonate users, a large control population and a combined total of 19,881 cases of esophageal cancer among bisphosphonate users and controls. Some studies controlled for known esophageal cancer risk factors such as alcohol consumption, smoking, body mass index, use of medications known to increase the risk for esophageal cancer and diagnosis of Barrett’s esophagus.

Analysis of these studies revealed that bisphosphonate users and nonusers had a similar risk for developing esophageal cancer (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.91-1.39; P not significant). Furthermore, in a subgroup

analysis of the duration of treatment, the risk for esophageal cancer was not significantly higher if these medications were used for less than one year or for more than three years.

Hans Gerdes, MD, attending physician at the Gastroenterology and Nutrition Service and director of the GI Endoscopy unit at Memorial SloanKettering Cancer Center, New York City, said that the results were in line with findings from most studies on the topic and therefore were “somewhat reassuring.” But he noted that the majority of the studies included have “relatively short” follow-up periods, and “it remains unclear whether chronic and prolonged

‘While awaiting further studies, clinicians should use bisphosphonates cautiously.’

—Saowanee Ngamruengphong,

Statins continued from page 24

with about a 30% reduction in risk for developing esophageal cancer.

In a subset of patients with known BE, statin therapy was associated with a 41% reduction in the risk for esophageal cancer (OR, 0.59; 95% CI, 0.45-0.78). The subset was drawn from five studies that included 312 cases of cancer in a population of 2,125 patients with BE. In this analysis, the reduction was highly consistent across all five studies, and the relative protection from esophageal cancer increased with longer duration of statin use. Moreover, in those taking both statins and NSAIDs or aspirin, the reduction in risk for esophageal cancer reached 72% relative to those patients taking neither therapy (OR, 0.28; 95% CI, 0.14-0.56).

The mechanism of protection from cancer is unclear, but it is hypothesized that neoplastic transformation may be mediated by anti-inflammatory, anti-proliferative or anti-apoptotic effects.

Dr. Singh noted that several observational studies have associated statin use with a reduction in the risk for several other forms of cancer including malignancies of the prostate, liver and colon.

MD

Due to the association of esophageal cancer and BE, the protection associated with statins in these observational studies may be sufficient to warrant the placebo-controlled study needed to confirm benefit. Even in this population, however, it may be helpful to select those at highest risk.

“We are now looking for markers that may be useful for predicting benefit from statin therapy,” said Dr. Singh, who suggested that this might be a useful step toward a randomized trial. One such potential biomarker is activated prostaglandin E2, which is associated with resistance to apoptosis, increased angiogenesis and enhanced invasion in Barrett’s mucosa, making it a potential surrogate marker for future development of esophageal cancer in Barrett’s mucosa. Although other signals may be considered, one of the barriers to randomized trials is developing a practical and specific statin regimen with a high likelihood of offering protection.

“Using data from observational studies, we are unable to estimate the effective dose, the duration or the best time to start statins in order to obtain chemoprevention,” Dr. Singh said.

Asked to comment on these findings, Michael Simon, MD, MPH, Karmanos Cancer Institute, Wayne State University in Detroit, said that they

use of bisphosphonates for five to 10 years is similarly safe.”

Nevertheless, the results are particularly relevant for gastroenterologists because patients with chronic reflux disease, who have the highest risk for esophageal cancer, also are more likely to be administered bisphosphonates, Dr. Gerdes said.

“There are retrospective studies showing that chronic use of proton pump inhibitors, a mainstay of medical treatment for chronic reflux [disease]— which is itself a risk factor for Barrett’s esophagus and esophageal cancer—can increase the risk for bone fractures,” Dr. Gerdes said. “These patients may then be told to undergo monitoring for osteopenia and osteoporosis and may receive bisphosphonates to prevent future bone complications.”

Regarding the limitations of existing research on the topic, Dr. Ngamruengphong said that large, well-designed prospective studies are still needed.

“While awaiting further studies, clinicians should use bisphosphonates cautiously,” she said.

■ Dr. Ngamruengphong reported no conflicts of interest. Dr. Gerdes has served as a consultant for Helsinn Birex Pharmaceuticals.

are “consistent with other literature that suggest a reduction in risk for cancer associated with statins.” Although he cautioned that data generated from a meta-analysis cannot be considered conclusive, “they are intriguing and provide hope for a cancer for which no other definitive primary prevention exists and which usually presents at an advanced and incurable stage.”

Dr. Simon has published data showing a correlation between statin use and a reduced risk for colorectal cancer, and he encouraged efforts to substantiate evidence of a protective effect for esophageal and other gastrointestinal cancers. However, as the proportion of patients on statins increases with age, their use is particularly widespread in most groups at high risk for esophageal cancer. Dr. Simon noted that any protective effect of statins against cancer would be added to the already substantial role of statins in reducing the risk for cardiovascular disease.

However, he cautioned that definitive trials would be challenging.

“Randomized studies of statins may be difficult because these drugs are already taken by such a large proportion of the population,” Dr. Simon said.

■ Drs. Singh and Simon reported no conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Experts Call for More Effective Screening Paradigm To Determine Esophageal Cancer Risk

BY CAROLINE HELWICK SAN FRANCISCO—It is impossible to identify every patient who is at risk for esophageal adenocarcinoma, but there are criteria that can help to craft a selective screening algorithm, experts told meeting attendees of the 2013 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

Most gastroenterologists tend to screen 54-year-old white men who smoke; have a body mass index (BMI) greater than 35 kg/m2; have a history of myocardial infarction, hypertension and lipidemia; have had heartburn for five years that has worsened in the last year; and report a family history of esophageal cancer. However, most cases are less straightforward, and clinical judgment is important in deciding whether or not to screen, said Kenneth Wang, MD, professor of medicine and director of the Advanced Endoscopy Group and Esophageal Neoplasia Clinic and a consultant in the Division of Gastroenterology and Hepatology at Mayo Clinic, Rochester, Minn.

The most important surrogate marker for the development of esophageal adenocarcinoma is Barrett’s esophagus (BE), but no guidelines recommend mass screening for BE or esophageal adenocarcinoma.

Surveillance is the current standard of care, and “it’s not that cost-effective because of the low incidence of esophageal adenocarcinoma,” said Dr. Wang.

“A large amount of resources is being spent on practices that are of little benefit, such as surveillance. I suggest we probably need to change our screening paradigm.”

were detected in subsequent years of the study, yielding an incidence rate for adenocarcinoma of 1.2 cases per 1,000 person-years. When compared with the risk in the general population, BE patients had a relative risk of 11.3; however, the annual risk was only 0.12%, and slightly higher in patients with dysplasia. The authors suggested their findings “call into question the rationale for ongoing surveillance in patients who have Barrett’s esophagus without dysplasia.”

norm for most patients with BE-related cancer (Gibbs JF et al. J Natl Med Assoc 2007;99:620-626).

“This means there is not much we can do,” said Dr. Wang.

Although the incidence of esophageal adenocarcinoma associated with gastroesophageal reflux disease (GERD) is increasing, it is rising much more slowly than the incidence of other cancers, “and this causes problems for screening,” Dr. Wang said. “Something needs to be done,

‘A large amount of resources is being spent on practices that are of little benefit, such as surveillance. I suggest we probably need to change our screening paradigm.’

—Kenneth Wang, MD

‘This is a difficult field. We like to find lesions early, but on the other hand our current paradigms don’t allow this because we are screening so many

To Screen or Not To Screen

individuals who don’t

The benefits of screening for BE are that earlier-stage disease is more curable; the precursor lesion is well known and easily recognized; and ablation therapy can reduce cancer risk, Dr. Wang said.

However, screening for BE is not particularly effective as a means of preventing esophageal cancer, largely because these cancers usually occur in the absence of BE, Dr. Wang noted.

For example, in a recent study of the Danish population, 93% of individuals found to have esophageal cancer had never been diagnosed with BE (Hvid-Jensen F et al. N Engl J Medd 2011;365:1375-1383).

Screening identified 11,028 individuals with BE, of whom 131 were diagnosed with adenocarcinoma within the first year of index endoscopy and 66 more cases

need it and not screening the ones who do need it.’

—Nicholas Shaheen, MD, MPH

“Barrett’s esophagus only accounted for 7% of the adenocarcinomas,” Dr. Wang said. “So if we do everything we talk about doing, we cannot affect the natural course of this disease for 93% of persons who develop cancer.”

Additionally, the lack of a history of reflux disease for 50% of individuals with BE creates a problem in identifying those at risk (Ronkainen J et al. Gastroenterology 2005;129:1825-1831), and a latestage symptomatic presentation is the

but we must do this in context of the risk [for] cancer in general.”

Evaluating Risk for BE The American Gastroenterological Association’s guidelines recommend selective screening for BE for individuals with the following risk factors: aged 50 years or older; male (odds ratio [OR], 1.5-3.0); white (OR, 4-6); chronic GERD (OR, 6-10, dose response); hiatal hernia (OR, 2.1); BMI >25 kg/m2 (OR,

1.4 for BMI 25-30 kg/m2); and intraabdominal distribution of body fat (OR, 2.8 for all BE, 4.3 for long-segment BE).

Elaborating on these risk factors, Dr. Wang said that the duration of reflux disease is linearly related to the risk for BE, with the risk rate exceeding 20% after 10 years of continual symptoms. Also, reflux symptoms and BE are affected by obesity and tobacco use. Central obesity appears to predispose an individual to BE, and low adiponectin levels also have been associated with it. Factors generated by obesity, especially inflammatory markers such as cytokines, are believed to stimulate pathways associated with cancer cell promotion and progression. The cell of origin in BE appears to be stem cells in the gastric cardia that migrate under the influence of inflammatory mediators to produce columnar metaplasia.

Many patients claim to have a family history of BE. The inheritance pattern appears to be autosomal dominant; however, a recent study suggested that only individuals with more than one affected family member have BE that is “familial,” Dr. Wang said.

“Those with only one affected family member do not seem different in terms of patient characteristics (e.g., obese or not), age at diagnosis of cancer and so forth.

We can use this information when we think about screening, that is, consider screening individuals who have more than one first-degree relative with BE.” The need to document the presence of intestinal metaplasia in esophageal biopsies from a columnar-lined esophagus (CLE) to diagnose BE is debated, Dr. Wang noted. The longer the CLE length, the more likely the presence of intestinal metaplasia, he said.

A recent study prospectively evaluated the prevalence and risk factors for CLE in a large cohort (N=1,058) of patients with GERD undergoing upper endoscopy (Balasubramanian G et al. Am J Gastroenteroll 2012;107:1655-1661). On index endoscopy, the prevalence of CLE was 23.3%, whereas CLE with documented intestinal metaplasia was 14.1%.

On multivariate analysis, heartburn duration greater than five years, white race and hiatal hernia were independent predictors for CLE, and CLE length was significantly associated with the presence of intestinal metaplasia. Family history of GERD or BE did not prove predictive of BE in the patients, Dr. Wang said.

Dr. Wang emphasized that using GERD as an indicator of risk is in itself problematic. see Screening, page 38

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Income continued from page 1

Variations in Compensation According to the survey, in 2012, 64% of gastroenterologists received an annual income between $200,000 and $499,999. Annual earnings varied considerably, with 19% making more than $500,000 and 18% receiving less than $200,000 (Figure 2). Nearly half of gastroenterologists surveyed (47%) said their income remained the same in 2012 compared with 2011. Compensation for employed gastroenterologists was based on salary, bonuses and profit-sharing earnings, but excluded payments for speaking engagements, expert witness testimony and product sales. The survey calculated compensation for private practice gastroenterologists after tax-deductible business expenses, but before income tax.

Nancy Reau, MD, a hepatologist and associate professor of medicine at The University of Chicago Medicine, in Illinois, was one of the 21,878 physicians who participated in the Medscape survey.

“Physicians do make a good living,” she said; however, this salary comes only after 10 to 15 years of training, which means physicians have to earn enough to pay off hundreds of thousands of dollars in student loans.

An additional stressor comes from declining professional fees, which have been diminishing across many specialties due to rising costs.

$405,000 $357,000 $349,000 $342,000 $340,000 $337,000 $317,000 $306,000 $279,000 $278,000 $276,000 $270,000 $268,000 $263,000 $263,000 $247,000 $242,000 $217,000 $186,000 $186,000 $185,000 $178,000 $175,000 $173,000 $170,000 ,

Orthopedics Cardiology Radiology Gastroenterology Urology Anesthesiology Plastic surgery Dermatology General surgery Oncology Ophthalmology Emergency medicine Critical care Nephrology Pulmonology Pathology Obstetrics/Gynecology Neurology Rheumatology Psychiatry Internal medicine Diabetes/Endocrinology Family medicine Pediatrics HIV/Infectious disease

$0

$100,000

$200,000

$300,000

$400,000

$500,000

Figure 1. Gastroenterologists are the fourth most highly compensated physicians.

30%

27% 25%

‘Procedurally oriented specialists, like gastroenterologists … have a large nut to

22% 19%

20%

cover: expensive office facilities, endoscope costs and recurring accreditation fees,

15%

15%

just to name a few. In order to stay afloat, productivity must increase.’

10%

10% 8%

—David Robbins, MD 5%

0%

$100,000 or less

$101,000 - $199,000 $200,000 - $299,000 $300,000 - $399,000 $400,000 - $499,000

$500,000 or more

Figure 2. Variation in financial compensation among U.S. gastroenterologists.

“This is especially true for procedurally oriented specialists, like gastroenterologists, who have a large nut to cover: expensive office facilities, endoscope costs and recurring accreditation fees, just to name a few,” said David Robbins, MD, associate director of the Center for Advanced Therapeutic Endoscopy at Lenox Hill Hospital in New York City. “In order to stay afloat, productivity must increase. Simply put, it’s human nature to not be happy working harder for less.”

The survey revealed regional variation in salary.

Gastroenterologists working in the Northwest earned the most, on average, making $498,000 annually.

In contrast, those who practice in the Northeast or Mid-Atlantic United States earned the least, making $319,000 and $311,000 per year, respectively (Figure 3).

Jerome Siegel, MD, clinical professor of medicine at Albert Einstein College of Medicine in New York City, noted that gastroenterologists who work in larger cities sometimes make less than those in smaller cities.

“If you read some of the ads or see requests from

headhunters, you would be amazed at how high the offers are to work in smaller communities, probably because of the lower overhead,” Dr. Siegel said. “For example, I have seen ads for gastroenterologists [in smaller cities] with offers exceeding $400,000, whereas, in New York [City], the usual starting salary is in the $225,000 range.”

Additionally, there was a notable salary gap between male and female gastroenterologists. Female gastroenterologists earned, on average, $308,000 annually compared with men who made $349,000, a discrepancy of approximately 30%. This salary difference, however, was less pronounced for gastroenterologists than for physicians in other specialties, where, on average, the gap was over 40% (Figure 4).

“Women routinely make about 20% less than their male counterparts across all fields, despite similar job descriptions,” Dr. Reau noted, noting that different definitions of job satisfaction between men and women may account for the salary discrepancy in medicine.

29

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Great Lakes $344,000

Northeast $319,000

Northwest* $498,000

North central $375,000

‘I think the general dissatisfaction comes not from the choice of career, but from

Southwest $404,000 West** $342,000

cuts in reimbursement and the hassles South central $356,000

Mid-Atlantic $311,000

Southeast $349,000

we confront with the “for-profit” insurance companies.’

—Jerome Siegel, MD

Job Satisfaction

* Includes Alaska ** Includes Hawaii

Figure 3. Financial compensation of gastroenterologists varies in different regions of the United States.

Image reprinted with permission from Medscape (http://www.medscape.com), 2013, available at: www.medscape.com/features/slideshow/compensation/2013/gastroenterology

$350,000

in an ACO or planned to join one in the coming year.

Almost 60% of gastroenterologists reported spending between 30 and 50 hours per week with patients. At the extremes of the spectrum, 11% of gastroenterologists said they spend less than 30 hours per week with patients, whereas 10% reported spending more than 60 hours per week. The majority of gastroenterologists (71%) saw between 25 and 99 patients per week; 7% had fewer than 25 patient visits per week, whereas 21% had 100 or more visits.

$349,000

Male Female

$308,000 $300,000

$259,000 $250,000

$199,000

$200,000 $150,000 $100,000 $50,000 $0 Gastroenterologists

All specialties

Figure 4. Male physicians earn more than female physicians.

“In medicine, many women have different descriptors of job satisfaction than men. Men might prefer a lucrative job, whereas women might prefer flexibility or the ability to work part time. To this end, I wouldn’t be surprised to see more part-time and salaried positions for women,” she said.

Dr. Siegel agreed: “The differential between male and female gastroenterologists is most likely related to the workload and input of time. Many women enter academia or take on regular clinic hours, which means a salaried position that is not open to the bonuses that private practice offers.”

Dr. Reau added that she also wouldn’t be surprised if men were more sophisticated with billing or things that might effect efficiency, whereas women might be less knowledgeable in these areas because they rank reimbursement lower in importance compared with other parts of the job.

Differences in Practice Setting The survey highlighted that gastroenterologists who work in health care organizations earned the most, on average, making $434,000 annually, compared with those who work in academia making the least, on average, at $236,000. In last year’s survey, gastroenterologists who worked in single-specialty, office-based groups were the highest earners; however, this year they placed third, at $381,000, behind gastroenterologists in multi-specialty group practices, at $421,000. Gastroenterologists in solo practice settings earned an average of $340,000 annually, followed by those in hospital settings at $264,000.

According to this year’s survey, 17% of gastroenterologists are involved in an accountable care organization (ACO)—a big uptick since last year’s 2%—whereas 9% said that they plan to join in the coming year. This number contrasted with last year’s survey, when only a combined 11% of gastroenterologists either participated

Given the chance to do it all over again, 58% of gastroenterologists said they would choose the same specialty compared with 42% of all physicians who completed the survey. Notably, fewer gastroenterologists—44%—would choose a career in medicine again compared with physicians of all specialties, at 51%. Twenty percent of gastroenterologists said they would pick the same practice setting.

“I think the general dissatisfaction comes not from the choice of career, but from cuts in reimbursement and the hassles we confront with the ‘for-profit’ insurance companies,” Dr. Siegel said. “Since I’ve been practicing for so long, I can tell you that the reimbursement for procedures I was doing in the early 1980s is close to 80% lower now.”

Furthermore, Dr. Siegel noted that gastroenterologists often wait six months or more to be reimbursed by insurance companies, which adds to the discontent.

According to the survey, gastroenterologists spend a fair amount of time handling paperwork and other administrative duties, which also likely affects their level of job satisfaction. Twelve percent of gastroenterologists reported dedicating 20 hours or more per week to paperwork and administrative tasks, and 42% said they spend 10 to 19 hours per week on such tasks.

“Medicine is not fun when one has to spend an inordinate amount of time writing appeals or calling poorly informed people representing [insurance] companies, and incurring additional expenses hiring more staff to handle reimbursement issues,” Dr. Siegel said. “If we had a single-payer system and could negotiate equitable fees for our services, the satisfaction ratio would improve. If we had satisfactory reimbursement for each procedure, there would be no paperwork. You file a claim and get paid.”

Indeed, the survey revealed that 12% of gastroenterologists plan to stop taking new Medicare or Medicaid patients, or to stop seeing current Medicare/Medicaid patients. Another 30% were undecided. Furthermore, 29% of gastroenterologists indicated that they plan to drop insurers who pay poorly or create the most denials and problems. However, 22% said that they needed to keep all insurers, and 20% felt that dropping insurers who pay poorly is inappropriate behavior.

Dr. Reau noted that the decline in satisfaction also is likely due to an increased threat of litigation. see Income, page 30

30

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Income continued from page 29

“Most gastroenterologists will be sued at least once in their lifetime,” she said. “And unfortunately, there is no complementary tort reform to protect gastroenterologists.

Being sued [or threatened with a lawsuit] can put a bitter taste in your mouth and impact how you practice.”

Increased requirements for documentation and quality reporting can hamper how gastroenterologists practice as well. During colonoscopies, for example, gastroenterologists must record insertion and withdrawal times, the number of polyps detected and document a plan of action after viewing each pathology report.

“If every night when you’re done seeing patients, you have to sign off on all dictations, your work basically doubles,” Dr. Reau said. “This process really has an impact on your mental happiness, and may explain why so many gastroenterologists said they wouldn’t return to medicine.”

However, Barbara Frank, MD, clinical professor of medicine at Drexel University College of Medicine in Philadelphia, said she has not witnessed reduced job satisfaction among the faculty or fellows she has encountered.

“There are some aspects of frustration [which one might encounter in any profession], but I have not seen a decrease in job satisfaction.” In fact, Dr. Frank recalled the enthusiasm among gastroenterology fellows during a special lecture hosted by the Delaware Valley Society for Gastrointestinal Endoscopy.

“If anything, the fellows who attended were talking about how much fun they had doing their jobs,” she said.

Dr. Robbins agreed that “overall, gastroenterologists should enjoy tremendous job satisfaction because we can take care of our patients in a very tangible way, the

procedures are exciting and varied, and there’s no limit to patients or up to date on techniques and attending conhow much, or little, you can choose to work.” ferences. The survey is basically about business accolades, However, he added that the level of satisfaction is which I think is terrible.” likely dependent on a physician’s age or number of years Although Dr. Reau agreed that the survey does not in practice. capture the context behind the “For those who were numbers, she noted that part of in practice in the ‘golden ‘For those who were in practice understanding these results is era’ it’s easy to understand knowing what gastroenteroloin the “golden era” it’s easy to why job satisfaction scores gists consider to be important are on the decline. But for understand why job satisfaction about their job or what their new gastroenterologists, scores are on the decline. But for new primary concerns are. many of whom are part “If patient interaction is at the of group practices and/or gastroenterologists … the golden era top of the list, then that physiambulatory surgery cen- is but a fable, and job satisfaction cian is probably OK making a ters, in which cost sharing bit less, whereas if money is the probably remains pretty high.’ and group bargaining may greatest driving force, then job —David Robbins, MD satisfaction will be closely tied mitigate the sting from a declining fee schedule, the to earnings,” she said. golden era is but a fable, Dr. Robbins attributed disand job satisfaction probably remains pretty high.” content among gastroenterologists partly to the “grass is always greener” sentiment.

A Grain of Salt “But I take a more optimistic tack and make time outAlthough the data are provocative, the gastroenterolo- side of medicine to pursue any number of hobbies,” he gists interviewed by Gastroenterology & Endoscopy News noted. were careful not to overinterpret the information.

A work–life balance also appeals to Dr. Reau, who “Surveys are OK, but they don’t tell the whole story,” added: “I love my job and I get to spend time with my Dr. Siegel noted. family. I make a good living and have the ability to do Dr. Robbins agreed that the survey may be useful in things outside of the daily grind, like go to conferences “broad strokes.” and travel.”

Dr. Frank, however, found the data lacking in value.

The full report is available from Medscape at www.

“Truthfully, the survey doesn’t deal with anything medscape.com/features/slideshow/compensation/2013/ of value to the specialty,” she said. “The survey mostly gastroenterology.

■ focuses on money. It doesn’t look at whether gastroenterologists are doing research or if they’re good to their —Additional reporting by Cynthia J. Gordon, PhD

OPINION

The Sunshine Act and You Frederick L. Greene, MD Clinical Professor of Surgery UNC School of Medicine Chapel Hill, North Carolina

As a feature of the Affordable Care Act (ACA), the Centers for Medicare & Medicaid Services (CMS) announced the final rendition of the Physician Payments Sunshine Act on Feb. 1. This portion of the ACA establishes a legal mandate and mechanism for physicians, group purchasing organizations and teaching hospitals to report when an economic benefit—$10 or greater—is provided from applicable manufacturers of pharmaceuticals, biologics and medical devices. These transactions will be collected beginning Aug. 1, 2013 and will be posted on a CMS public website beginning Sept. 30, 2014.

Although there is no mandatory reporting by physicians, it would seem prudent that we all must be aware that acceptance of monetary or in-kind items makes us vulnerable for public listing. It is obvious that the busy academic or private practice surgeon may overlook minor gifts, honoraria or consulting fees. Because our information (name, address, license number and specialty) will be posted on a public website, it should at least be listed for correct reasons. Fortunately, the Sunshine Act allows a 45-day opportunity to resolve any disputes relating to

improper reporting to physicians by the offering entity. and resident teaching, I have consistently recommended After this “corrective period,” information becomes pub- to pharmaceutical and device companies that “in-kind” licly available in cyberspace. giving be considered in the form of books, videos and It is obvious that many physicians reading this col- other educational tools. It is still unclear to me even after umn have been and/or will be the recipient of some reading the Sunshine Act whether the teaching institumonetary or in-kind award of $10 or greater from some tion, the trainees or I would be considered the prime company. For many of us, consulrecipients. Although residents are frequently targeted by meditation and speaking fees, research grants, meeting support, books, When September 2014 rolls cal companies offering material videos etc., exceed the $10 mini- around and data become benefits, it does not appear that mum by a significant amount. All trainees will be publicly reported. of us will need to look periodically publicly reported, part of our As we go forward, we need to at the CMS site and at these dol- responsibility will be to ask be aware that any relationship, lar values to ensure that reporting even minor, will be made public companies if what we receive is both correct and appropriate and potentially scrutinized. My on this public site after Sept. 30, will be reported and then to hope is that this type of govern2014. This is particularly impor- keep a careful eye on the ment activity will not adversely tant for any physician who has a affect the positive relationship financial interest in a pharmaceu- CMS website. that has existed for decades tical or device manufacturer or between physicians and drug and group purchasing organization. device makers, but I would be My message to all is to keep your own records so that naive to assume this conclusion. I also wonder who or any need to justify inaccurate reporting or conflicting what agencies will keep close scrutiny on this reported information can be corrected. No doubt this will be a information. I do know that when September 2014 rolls burden, and will potentially widen the gap between our around and data become publicly reported, part of our manufacturing colleagues and us. I have always been a responsibility will be to ask companies if what we receive proponent of open access to drug and device represen- will be reported and then to keep a careful eye on the tatives. Because of my experience in academic surgery CMS website.

■

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32

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Cost Sharing continued from page 1

Atlanta. “There have been a number of anecdotal reports by gastroenterologists and primary care physicians about patients getting unexpected bills for polypectomy when they were told there would be no cost associated with it. And since a polyp removed during the course of a screening colonoscopy may well prevent cancer, we want to do all that we can to encourage that being done. So this is a step in the right direction.”

However, the provision does not extend to Medicare recipients, who will still be responsible for cost sharing when a screening exam turns therapeutic.

“Almost 93% of CRC [colorectal cancer] will be diagnosed in people over the age of 50, and a large proportion of those are diagnosed after the age of 65 years—Medicare beneficiaries,” said March Seabrook, MD, a practicing gastroenterologist at the University of South Carolina School of Medicine and chair of the National Affairs

Committee for the American College of Gastroenterology (ACG). “This is the group we really need to make sure is covered adequately.”

The provision applies only to nongrandfathered health plans, defined by the U.S. Department of Health and Human Services (HHS) as plans that were not in existence at the time the ACA was signed into law on March 23, 2010. Grandfathered plans—those in existence prior to March 23, 2010— could lose their grandfathered status if

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they make major changes in coverage and cost sharing, or join the forthcoming state-based health exchanges beginning in 2014. The HHS estimates that 40% to 60% of grandfathered plans will lose their status but the remainder could retain their grandfathered status, even after 2014.

Although the provision will apply to plans that were new to the system after March 2010 and to plans participating in state-based health exchanges, some will be exempt, such as large employer health plans (those covering 100 or more employees) that will not be allowed to participate in the exchanges until 2016.

Private plans must disclose to their beneficiaries whether or not the plan is grandfathered, but it may not occur to patients to inquire.

It is not clear whether the elimination of cost sharing will increase the rate of CRC screening, which is currently between 55% and 58% for Medicare beneficiaries.

‘There have been a number of anecdotal reports by gastroenterologists and primary care physicians about patients getting unexpected bills for polypectomy when they were told there would be no cost associated with it. And since a polyp removed during the course of a screening colonoscopy may well prevent cancer, we want to do all that we can to encourage that

GI Anatomy Notepads — Patient Education Tool!

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nderstand patient tools. ASGE’s new GI Anatomy Notepads are the perfect take-home visual aid for explaining conditions and complex procedures to patients. Also available in Spanish. s 3MALL "OWEL s #OLON 2ECTUM s 5PPER 'ASTROINTESTINAL 4RACT s 0ANCREAS "ILE $UCTS 'ALLBLADDER

the right direction.’

Patient Education Brochures Educatte your patients with these self-explanatory and comprehensive takeaway brochures.

These brochures are written by GI endoscopists, for GI endoscopists. Titles include: #OLON NOSCOPY #OLON #ANCER 3CREENING 5PPER %NDOSCOPY 'ASTROESOPHAGEAL 2EmUX $ISEASE

0OLYP YPS AND THEIR 4REATMENT %2#0 #APSULE %NDOSCOPY %53 "ARRETT S %SOPHAGUS %NSURING Safety in Endoscopy plus many more! Some titles also available in Spanish.

Saf

Visit the ASGE Store at www.asge.org, or call (630) 573-0600 to find the resources you need to help your practice and your patients.

—Durado Brooks, MD, MPH

“High out-of-pocket costs are one barrier to CRC screening,” said Spencer Dorn, MD, MPH, assistant professor of medicine at the University of North Carolina School of Medicine in Chapel Hill.

“Under the original interpretation [of the ACA], if a polypectomy was performed, the procedure was reclassified as therapeutic and the patient became responsible for out-of-pocket costs. Fortunately, the HHS corrected this oversight by recognizing polypectomy as an integral part of a colonoscopy.

“I doubt that many patients understand

33

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

these arcane differences, so it is unlikely that the new rule will increase screening colonoscopy rates above and beyond how the ACA provision was originally interpreted,” Dr. Dorn noted. “Still, the new rule will eliminate surprise costs that were a common source of frustration for both patients and their gastroenterologists alike.”

effectiveness in lowering the rates of both CRC and CRC-related mortality, the reluctance of the government and private insurers to do everything possible to reduce the barriers to CRC screening has raised some questions.

Medical Semantics

and prefer to undergo a noninvasive stool test. That’s a screen,

When the ACA was first passed, it included some positive measures in terms of CRC screening. First, the new state-based private health insurance exchanges were required to provide preventive services, including colonoscopy, at no additional cost to patients. Second, for Medicare patients, the deductible, as well as the 20% Medicare beneficiary coinsurance, were waived for any CRC screening recommended by the U.S. Preventive Services Task Force. Also, the deductible is waived for any Medicare beneficiary’s screening when a polyp is removed.

However, due to the way procedures are coded, once a polyp is removed, a colonoscopy is no longer a screening exam, but a diagnostic or therapeutic one. Concerned about the wording of the ACA bill, representatives of the ACG, the American Society for Gastrointestinal Endoscopy (ASGE) and the American Gastroenterological Association (AGA) sought clarification from Congress and the Centers for Medicare & Medicaid Services (CMS).

“CMS looked at the section in the law that states cost sharingg is waived for recommended screenings, and the next section that states the deductible is waived for a screening that turns therapeutic,” an ACG representative.

“CMS then determined it did not have the regulatory authority to waive the Medicare beneficiary’s 20% coinsurance when a polyp is removed because Congress never used the word coinsurance, yet specifically chose the word deductiblee when a screening turns therapeutic,” the representative said, noting that this may have been an unintended quirk in the drafting of the statute. The ACG and others are currently advocating Congress to add the word “coinsurance” to the law.

Dr. Seabrook said, “If I, as a gastroenterologist, was smart enough to know that a person being referred for a screening colonoscopy did not have any polyps or any lesions of concern, I would not do the colonoscopy. But we’re just not that smart yet. We might be, with other diagnostic tests in the future, but for now the single best test to detect and remove precancerous polyps is a colonoscopy.”

Given colonoscopy’s established

treating advanced-stage CRC has risen dramatically in recent years. We’ve had a number of new drugs introduced that improve survival [rates], but those drugs come with a very high price tag.”

In addition to the cost sharing still

‘Some people choose not to undergo a screening colonoscopy

but if it turns out positive, suddenly that patient’s colonoscopy would not be considered a screening test and they’d be faced with a full coinsurance and deductible.’

—Durado Brooks, MD, MPH

‘We view [having] a colonoscopy [as a follow up to] a positive stool test as part of the screening process. Hopefully over time we can get the insurance companies and federal agencies to share that view and consequently remove the barrier to full evaluation of an abnormal screening test.’

—Durado Brooks, MD, MPH

“Many of us in this field have wondered about it for a long time,” said Dr. Brooks. “It’s been shown for many years that CRC screening is highly costeffective compared with other cancer screening tests, like mammography, and also compared with other public health measures. Additionally, the cost of

faced by Medicare recipients who initially choose to undergo colonoscopy for CRC screening, Dr. Brooks pointed to other colonoscopy-related cost concerns.

“Some people choose not to undergo a screening colonoscopy and prefer to undergo a noninvasive stool test. That’s a screen, but if it turns out positive,

suddenly that patient’s colonoscopy would not be considered a screening test and they’d be faced with a full coinsurance and deductible,” he said.

“We view [having] a colonoscopy [as a follow up to] a positive stool test as part of the screening process. Hopefully over time we can get the insurance companies and federal agencies to share that view and consequently remove the barrier to full evaluation of an abnormal screening test.”

‘Lowering Barriers and Raising Quality’ In May 2012, members of the ACG, ASGE, AGA, the American Cancer Action Network, Fight Colorectal Cancer and the National Colorectal Cancer Roundtable met with HHS to discuss the problem of cost sharing as a barrier to CRC screening, and to advocate for the elimination of that barrier. The groups were pleased when HHS and the U.S. Department of Labor released the clarification in February 2013 in the form of a list of frequently asked questions specifying that non-grandfathered insurance companies and those participating in exchanges must waive cost sharing when a polyp is removed during screening. But it appears that a statutory fix is required to extend this provision to Medicare beneficiaries.

In March, Rep. Charlie Dent (R-PA) introduced H.R. 1070, the Removing Barriers to Colorectal Cancer Screening Act of 2013, aimed at eliminating the unintended hidden costs of polyp removal during screening colonoscopy in Medicare beneficiaries. Also in March, Sen. Ben Cardin (D-MD) and Rep. Richard Neal (D-MA) introduced H.R. 1320, the Supporting ColoRectal Examination and Education Now (SCREEN) Act of 2013 into the House and Senate specifically to ensure that the waiving of cost sharing is extended to Medicare beneficiaries, and also to increase the quality of screening exams. For example, the SCREEN Act provides coverage for a prescreening visit, currently not covered

by Medicare, and also provides an incentive for voluntary participation by health care professionals in one of the nationally recognized quality improvement registries. Gastroenterologists whose services do not measure up to the accepted standards of care as defined by their peers will be reimbursed at a lower rate.

“As gastroenterologists in the ACG, we support the effort to lower the barriers to CRC screening as well as raise the quality of the examination,” Dr. Seabrook said. “That’s my new mantra: lowering barriers and raising quality.”

■

Q & A

34

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

A D V E R T I S E M E N T

Santarus Introduces Uceris for Ulcerative Colitis

Q.

What is UCERIS

TM

(budesonide)?

A.

UCERIS is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis (UC).1

Q.

How is UCERIS different from other corticosteroids?

A. UCERIS contains budesonide, a locally acting corticosteroid.1 Budesonide is a highly potent corticosteroid that is rapidly metabolized, and therefore must be delivered to its desired site of action for optimal effect.2

Q.

What are the main differences between UCERIS and Entocort® EC?

A. UCERIS is indicated for the induction of remission in patients with active, mild to moderate UC.1 Entocort® EC is indicated for the treatment of Crohn’s disease—not UC.3 UCERIS, with MMX® technology, dissolves at pH ≥7, the approximate pH level near the entry to the colon.1,4 UCERIS is designed for targeted local delivery throughout the full length of the colon.1,5 Entocort® EC uses a controlled-release technology and is designed to dissolve at pH ≥5.5, the approximate pH of the duodenum.3

Q.

Is UCERIS effective?

A. Yes. Three times as many patients taking UCERIS achieved the stringent combined primary end point of clinical remission and mucosal healing as patients receiving placebo (18% vs. 6%, respectively). Relatively few

patients receiving placebo achieved the combined primary end point, further illustrating the challenge in meeting this stringent end point.6*

Q.

Is UCERIS safe?

A. There were no clinically significant differences in glucocorticoid-related side effects between UCERIS 9 mg and placebo at eight weeks.* Additionally, there were no clinically significant differences in glucocorticoid-related side effects between UCERIS 6 mg and placebo at 12 months. (The UCERIS long-term safety study used 6 mg as a potential maintenance dose.1 The 6-mg dose is not currently approved in the United States.) Abnormally low bone density also was reported at similar rates for UCERIS 6 mg and placebo.6 The most common adverse reactions (incidence ≥2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia and constipation.1

Q.

Is UCERIS convenient?

A. Yes! UCERIS is a single 9-mg tablet taken once daily in the morning for up to eight weeks. Additional eight-week courses of UCERIS can be given for recurring episodes of active disease.1

References 1. UCERIS Prescribing Information. San Diego, CA: Santarus, Inc.; January 2013.

2. Sandborn WJ, Travis S, Moro L, et al. Oncedaily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.

Gastroenterology. 2012;143(5):1218-1226.

3. Entocort Prescribing Information. AstraZeneca AB; December 2011.

4. Press AG, Hauptmann IA, Hauptmann L, et al. Gastrointestinal pH profiles in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 1998;12(7):673-678.

5. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol.

2006;61(1):31-38.

6. Data on file. San Diego, CA: Santarus, Inc. UCERIS is a trademark of Santarus, Inc. Entocort® EC is a registered trademark of AstraZeneca GmbH. MMX is a registered trademark of Cosmo Technologies Ltd.

Please see Important Safety Information and Brief Summary of Prescribing Information on the following pages. * In a pooled analysis of two Phase III trials.1,6

Younger Women With Endometrial Cancer At Increased Risk for Colorectal Cancer Data Suggest Earlier CRC Screening in This Population

BY DAVID WILD LAS VEGAS— —Women diagnosed with endometrial cancer before the age of 50 years are nearly seven times more likely than younger individuals without this cancer to develop right-sided colorectal cancer (CRC), according to findings from a large case–control study. Experts believe the heightened risk for CRC may be due to underlying Lynch syndrome, which is present in an estimated 10% of younger patients with endometrial cancer.

“These findings strongly suggest that this endometrial–colon cancer association arises because of Lynch syndrome,” said Randall Burt, MD, who was not involved in the study, and is director of the Familial Colon Cancer Clinic and co-director of the Family Cancer Assessment Clinic at Huntsman Cancer Institute in Salt Lake City.

Testing younger patients with endometrial cancer for the syndrome and also inquiring about a history of endometrial cancer during CRC screening may be warranted, said Dr. Burt, who is also a professor in the Division of Gastroenterology at the University of Utah School of Medicine, Salt Lake City.

“A number of centers, including our own, now do

tumor testing for microsatellite instability and conduct immunochemistry of mismatch repair genes on all newly diagnosed endometrial cancer cases,” he said.

The findings, which were first presented at the 2012 American College of Gastroenterology Annual Scientific Meeting, were recently published in the Journal of Clinical Oncology (Singh H et al. 2013 Apr 8.

[Epub ahead of print]). Lead investigator Harminder Singh, MD, a clinician scientist and assistant professor of medicine in the Departments of Internal Medicine and Community Health Sciences at the University of Manitoba, Canada, and his colleagues examined data from 3,115 women diagnosed with endometrial cancer between 1987 and 2008 who were registered in several large, longitudinal databases in Manitoba. They compared the incidence of subsequent CRC in this group with up to five age-matched female controls with no history of invasive cancer on the index date. The total follow-up period included 145,502 patient-years. Analyses were controlled for age, history of lower gastrointestinal endoscopy and socioeconomic status.

The researchers found that women diagnosed with endometrial cancer as their first cancer, prior to the age of 50 years, were 4.4 times more likely than controls of

the same age to be diagnosed with CRC later on (hazard ratio [HR], 4.41; 95% confidence interval [CI], 1.4713.26). The risk was even higher when they looked only at the incidence of right-sided CRC (HR, 7.48; 95% CI, 1.29-43.28). The researchers did not find an increased risk for CRC among women diagnosed with endometrial cancer after age 50.

Dr. Singh said his study’s use of several databases, including a well-designed province-wide cancer registry, makes the findings reliable. Although the link between endometrial cancer and CRC risk needs to be more firmly established through pathology and genetic testing, Dr. Singh believes that “in the interim, colorectal screening may need to be considered at a younger age in these women.

“Universal testing for Lynch syndrome may be justified in endometrial cancer patients diagnosed at a younger age, and guidelines may need to be revised accordingly,” he said. “Additional studies should determine the risk for CRC in young women with endometrial cancer and no evidence of Lynch syndrome.”

■ Drs. Burt and Singh reported no relevant conflicts of interest.

READY FOR A

POWER IN UC?

In Active, Mild to Moderate Ulcerative Colitis (UC)1

INDICATIONS AND USAGE UCERISâ&#x201E;˘ is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. t *ODSFBTFE TZTUFNJD HMVDPDPSUJDPJE TVTDFQUJCJMJUZ 3FEVDFE MJWFS DOSAGE AND ADMINISTRATION function affects the elimination of glucocorticosteroids.

The recommended dosage for UCERIS is one 9-mg tablet to be taken t 0UIFS HMVDPDPSUJDPJE FGGFDUT $BVUJPO TIPVME CF UBLFO JO QBUJFOUT once daily in the morning with or without food for up to 8 weeks. with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or IMPORTANT SAFETY INFORMATION glaucoma, or with any other condition where glucocorticosteroids CONTRAINDICATIONS may have unwanted effects.

UCERIS is contraindicated in patients with known hypersensitivity ADVERSE REACTIONS to budesonide or any of the ingredients of UCERIS. Most common adverse reactions (incidence â&#x2030;Ľ2%) are headache, WARNINGS AND PRECAUTIONS nausea, decreased blood cortisol, upper abdominal pain, fatigue, t )ZQFSDPSUJDJTN BOE BESFOBM TVQQSFTTJPO 4JODF 6$&3*4 JT B flatulence, abdominal distension, acne, urinary tract infection, glucocorticosteroid, general warnings concerning glucocorticoids arthralgia, and constipation. should be followed.

DRUG INTERACTIONS t 5SBOTGFSSJOH QBUJFOUT GSPN TZTUFNJD DPSUJDPTUFSPJET Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from juice). May cause increased systemic corticosteroid effects. systemic corticosteroids if transferring to UCERIS. USE IN SPECIFIC POPULATIONS t *NNVOPTVQQSFTTJPO 1PUFOUJBM XPSTFOJOH PG JOGFDUJPOT FH )FQBUJD JNQBJSNFOU .POJUPS QBUJFOUT GPS TJHOT BOE PS TZNQUPNT existing tuberculosis, fungal, bacterial, viral, or parasitic of hypercorticism.

CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: â&#x2030;Ľ4 and â&#x2030;¤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of â&#x2030;¤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a â&#x2030;Ľ1-point reduction in the endoscopic index score) after 8 weeks of treatment.1

UCERIS™:

A POWERFUL, LOCALLY ACTING STEROID1-3 t MMX® technology targets delivery of budesonide throughout the full length of the colon1,2 t 3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo3*

A SAFETY PROFILE THAT OFFERS CONFIDENCE1 t The rates of overall expected glucocorticoid-related side effects were similar for UCERIS and placebo at 8 weeks— 10.2% vs 10.5%, respectively1*

www.UCERIS.com The Important Safety Information does not include all of the information needed to use UCERIS safely and effectively.

Please see Brief Summary of Prescribing Information on the following page and Full Prescribing Information at www.UCERIS.com. *In a pooled analysis of 2 Phase III clinical trials.1,3 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38. 3. Data on file. Santarus, Inc. UCERIS is a trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd.

© 2013 Santarus, Inc. 1-UCE13089 January 2013 Printed in the USA.

38

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2013

Thiopurine Use Associated With â&#x20AC;&#x2DC;Small But Real Riskâ&#x20AC;&#x2122; For Non-Hodgkin Lymphoma in UC â&#x20AC;&#x2DC;The absolute risk for lymphoma

BY TED BOSWORTH LAS VEGASâ&#x20AC;&#x201D;Continuous use of thiopurines in patients with ulcerative colitis (UC) increases the risk for lymphoma almost threefold, according to a retrospective cohort study of a large nationwide database.

BRIEF SUMMARY Please see package insert for Full Prescribing Information available at www.uceris.com UCERIS (budesonide) extended release tablets, for oral use Rx Only INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations.

WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur.

Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections.

Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: t )ZQFSDPSUJDJTN BOE "ESFOBM 4VQQSFTTJPO t 4 ZNQUPNT PG TUFSPJE XJUIESBXBM JO UIPTF QBUJFOUT USBOTGFSSJOH from Systemic Glucocorticosteroid Therapy t *NNVOPTVQQSFTTJPO t * ODSFBTFE 4ZTUFNJD (MVDPDPSUJDPTUFSPJE 4VTDFQUJCJMJUZ t 0UIFS (MVDPDPSUJDPTUFSPJE &GGFDUT Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo.

They ranged in age from 18-77 years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1.

Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2)

Headache Nausea Decreased Blood Cortisol Upper Abdominal Pain Fatigue Flatulence Abdominal Distension Acne Urinary Tract Infection Arthralgia Constipation

UCERIS 9 mg (N = 255) n (%) 29 (11.4) 13 (5.1)

UCERIS 6 mg (N = 254) n (%) 37 (14.6) 12 (4.7)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3)

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

8 (3.1) 6 (2.4) 6 (2.4) 6 (2.4) 5 (2.0) 5 (2.0) 5 (2.0)

5 (2.0) 8 (3.1) 4 (1.6) 2 (0.8) 1 (0.4) 5 (2.0) 1 (0.4)

5 (1.9) 5 (1.9) 2 (0.8) 5 (1.9) 1 (0.4) 4 (1.6) 2 (0.8)

The study, one of the largest in this field to date, included data from 36,826 patients with UC who were treated in the Southeast Louisiana Veterans Health Care System in New Orleans, over a 10-year period. Study author, Ali Abbas, MD, MPH, presented the findings at the annual meeting of the American College of Gastroenterology.

0G 6$&3*4 NH QBUJFOUT B UPUBM PG EJTDPOUJOVFE USFBUNFOU EVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies.

Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

0WFSBMM Mood changes Sleep changes Insomnia Acne Moon face Fluid retention Hirsutism Striae rubrae Flushing

UCERIS 9 mg (N = 255) n (%) 26 (10.2) 9 (3.5) 7 (2.7) 6 (2.4) 6 (2.4) 3 (1.2) 2 (0.8) 1 (0.4) 0 0

UCERIS 6 mg (N = 254) n (%) 19 (7.5) 10 (3.9) 10 (3.9) 6 (2.4) 2 (0.8) 3 (1.2) 3 (1.2) 0 0 1 (0.4)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3) 12 (4.7) 8 (3.1) 5 (1.9) 4 (1.6) 3 (1.2) 0 2 (0.8) 3 (1.2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating UCERIS 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1), but had not achieved remission. Among patients who took UCERIS 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took UCERIS 9 mg for 8 weeks in Study 1.

In Study 4, the safety of long-term treatment with UCERIS 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to UCERIS 6 mg or placebo once daily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and UCERIS 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the UCERIS 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects were similar in patients with up to 12 months of therapy with UCERIS 6 mg and placebo. (Table 3) Table 3. Summary of Glucocorticoid Related Effects Over 12-month Treatment (Study 4)

0WFSBMM Insomnia Mood changes Moon face Sleep changes Acne Hirsutism Flushing Fluid retention

UCERIS 6 mg (N = 62) n (%) 9 (14.5) 4 (6.5) 4 (6.5) 3 (4.8) 3 (4.8) 3 (4.8) 3 (4.8) 1 (1.6) 1 (1.6)

Placebo (N = 61) n (%) 7 (11.5) 4 (6.6) 2 (3.3) 3 (4.9) 3 (4.9) 0 0 1 (1.6) 1 (1.6)

Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids).

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects:: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed.

Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable

Researchers divided patients into three groups: continuous users of thiopurines, discontinuous users of thiopurines and nonusers. The vast majority (87%) were nonusers. Of the 13% who had used thiopurines, only 15%â&#x20AC;&#x201D;or 2% of the total study populationâ&#x20AC;&#x201D;were continuous users.

Over a median follow-up of six years, to that in non-lactating women with asthma from other studies.

Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study.

The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study.

Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother.

Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients.

Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients.

OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

UCERISâ&#x201E;˘ is a trademark of Santarus, Inc. U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293,273. Š 2013 Santarus, Inc.

1-UCE13033 V1

remains very low. Patients with UC who are deriving significant benefit from their thiopurines

the incidence rate of lymphoma was 2.8 per 1,000 patient-years compared with 0.7 and 0.8 per 1,000 patient-years for the discontinuous users and nonusers, respectively. After adjusting for age, sex and race race, the hazard ratio for lymphoma risk for continuous users, relative to discontinuous users or nonusers, was 3.2 (95% confidence interval [CI], 1.6-6.0).

The vast majority of lymphomas were non-Hodgkin, with only 2% of cases representing Hodgkin lymphoma.

Previous studies have suggested that immunosuppressive drugs, particularly those used in inflammatory bowel disease (IBD), increase the risk for lymphoma. In a 2010 literature review, a team from the United Kingdom concluded that the relative risk for lymphoma from thiopurines in patients with IBD may be increased four- or fivefold over no exposure to thiopurines

Screening continued from page 26

â&#x20AC;&#x153;It is hard to sort things out strictly on the basis of GERD,â&#x20AC;? he said.

In six studies that evaluated GERD as a predictor of BE, prevalence of BE ranged from 2% to 20% in individuals with GERD and from 1% to 25% in those without GERD. Dr. Wang also said that clinicians should remember that outcomes for BE are not always dire. Only 7% of BE patients died from esophageal cancer, according to a 2010 meta-analysis (Sikkema M et al. Clin Gastroenterol Hepatoll 2010;8:235-244). This finding has implications for the cost of surveillance, the study authors noted.

How To Proceed Dr. Wang predicted that future screening paradigms will be more specific and helpful, using genome-wide association

39

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

should probably continue these medications, given how few effective IBD medications we have.’

—Athos Bousvaros, MD, MPH

should be considered in relation to a small, but significant, increased risk for lymphomas when these agents are used continuously.

According to Athos Bousvaros, MD, MPH, assistant professor and associate director, IBD Center, Boston Children’s Hospital, the data presented by Dr. Abbas and his co-investigators are consistent with other published data, including a recent study by Ashworth et al (Inflamm Bowel Dis 2012;18:838843) and an earlier study by Beaugerie et al (Lancett 2009;374:1617-1625).

NEW (Smith MA et al. Aliment Pharmacoll Therr 2010;32:119-130), but they also noted that the absolute risk remained low. They estimated one additional lymphoma for every 300 to 1,400 years off thiopurine treatment. treatment Reports also have been published that have associated thiopurines with increased risk for nonmelanoma skin cancer (Setshedi M et al. J Gastroenterol Hepatoll 2012;27:385-389). However, the studies that associated thiopurines with skin cancer—similar to the studies that associated these immunomodulatory agents with lymphoma—all have been retrospective. In such retrospective studies, it is possible that inadequate control for relevant factors, such as exposure to other agents with cancer-promoting effects, have influenced the association.

However, these findings suggest that the benefit of thiopurines for UC control

studies to select patients for screening and to estimate prognosis. Meanwhile, he said that screening should be selective and targeted to appropriate highprevalence groups and individuals whose family history includes two or more firstdegree relatives.

Commenting on Dr. Wang’s presentation, Nicholas Shaheen, MD, MPH, professor of medicine and epidemiology and director of the Center for Esophageal Diseases & Swallowing at the University of North Carolina School of Medicine in Chapel Hill, said, “This is a difficult field. We like to find lesions early, but on the other hand, our current paradigms don’t allow this because we are screening so many individuals who don’t need it and not screening the ones who do need it. We need to develop new ways of being able to screen large numbers of people inexpensively, so we can eliminate GERD as a predicate for screening.” ■

Based on the preponderance of these data, Dr. Bousvaros said that it is now fair to conclude that “thiopurine use is associated with a small but real risk for the development of non-Hodgkin’s lymphoma.” In regard to this particular study, he noted that one “novel piece of information is that discontinuous use (or discontinuation of the medication) may reduce the risk for lymphoma.”

From a practical and clinical point of view, however, Dr. Bousvaros said, “The absolute risk for lymphoma remains very low. Patients with UC who are deriving

significant benefit from their thiopurines should probably continue these medications, given how few effective IBD medications we have.”

Dr. Bousvaros added that “clinicians might want to consider other options in patients who have not seen benefit from thiopurine treatment after a reasonable trial,” which he defined as a few months of thiopurines administered at a therapeutic level.

■ Drs. Abbas and Bousvaros reported no conflicts of interest.

In bowel preparation

The NEW Combination Makes the Difference Introducing Suclear Provides the flexibility and convenience of two dosing regimens (same-day, split-dose), with success* achieved in 90% of patients1,2 Significantly more “excellent” preps* with Suclear vs HalfLytely (47.7% vs 35.6%, respectively; P=0.01†) in same-day dosing comparison1 – Prep time was 33% less with Suclear compared to HalfLytely (3.7 hours vs 5.5 hours, respectively; P<0.001†)1 Equivalent rates of excellent cleansing* between Suclear and MoviPrep®‡ (51.9% vs 51.4%, respectively) in split-dose comparison1 Cecum reached in almost all patients using Suclear (split-dosing: 100%; same-day dosing: 99%)1 * *Based on investigator grading. † Statistically significant difference. ‡ MoviPrep [PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution] is a trademark of the Norgine group of companies.

IMPORTANT SAFETY INFORMATION Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution) is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended (sodium sulfate, potassium sulfate, and magnesium sulfate final volume.

NEW

Please see brief summary of Full Prescribing Information on adjacent page.

oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

40

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Combination Therapies, but Not Adalimumab Alone, Increase Risk for Cancer in IBD Patients Data Implicate Thiopurines in Risk for Nonmelanoma Skin Cancer

BY DAVID WILD HOLLYWOOD, FLA.—Patients with inflammatory bowel disease (IBD) who are receiving combination therapy with immunomodulators and adalimumab are five times more likely than those in the general population to develop nonmelanoma skin

cancer (NMSC), a pooled analysis has found. Results also showed that adalimumab alone did not heighten the risk for malignancies in patients with IBD compared with the general population.

Drawing on data from almost 1,600 patients, the findings fall in line with previous research, including studies conducted by Millie Long, MD, MPH,

assistant professor of medicine, Division of Gastroenterology and Hepatology at the University of North Carolina School of Medicine in Chapel Hill.

“This work shows that the risks with combination therapy are likely driven by thiopurines,” said Dr. Long, who was not involved in the current study.

The analysis was conducted by a team of investigators led by James

NEW (sodium sulfate, potassium sulfate, and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

Introducing Suclear The NEW combination for dosing flexibility High success rates in same-day and split-dose regimens1,2 Cecum reached in nearly 100% of patients1 Significantly less prep time compared to HalfLytely1 References: 1. Data on file. Braintree Laboratories, Inc., Braintree, MA. 2. Suclear [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2013.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution). INDICATIONS AND USAGE: A combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: Suclear is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended final volume. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 362 patients who took Suclear in clinical trials, 90 (25%) were 65 years of age or older, while 29 (8%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger subjects.

DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of each Suclear dose may not be absorbed completely.y Concurrent use of stimulant laxatives and Suclear may increase the risk of mucosal ulcerations or ischemic colitis. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Consume only clear liquids (no solid food or milk) and avoid alcohol on the day before colonoscopy until after completion of the colonoscopy. Split-Dose (2-Day) Regimen (Preferred Method): Dose 1 – Evening before the colonoscopy (10 to 12 hours prior to Dose 2): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Refill the container and drink another 16 oz. of water over the next 2 hours, and another before going to bed. Dose 2 – Next morning on the day of colonoscopy (start at least 3 ½ hours prior to colonoscopy): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Complete drinking the solution at least 2 hours before the colonoscopy. Consume only clear liquids until 2 hours prior to colonoscopy. Day-Before (1-Day) Regimen (Alternative Method): On the evening before the colonoscopy: Dose 1 (begin at least 3 ½ hours prior to bedtime): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Drink another 16 oz. of water over the next 2 hours. Dose 2 (approximately 2 hours after starting Dose 1): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Refill the container and drink another 16 oz. of water before going to bed. Consume only clear liquids until 2 hours prior to colonoscopy.

STORAGE: Store at 20-25°C (68-77°F). Excursions permitted between 15-30°C (59-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.braintreelabs.com ©2013 Braintree Laboratories, Inc.

SU-14168

March, 2013

Lewis, MD, MSCE, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia. Dr. Lewis and his colleagues analyzed data from several completed or ongoing studies of adalimumab for IBD treatment, including subpopulations that received adalimumab with azathioprine, mercaptopurine or methotrexate.

Cancer rates among 1,594 study participants with IBD, representing 3,050 patient-years, were compared with cancer rates in the general population as estimated in the Surveillance, Epidemiology, and End Results registry. Dr. Lewis’ team controlled for the possible effects of corticosteroid use, smoking status, baseline Crohn’s Disease Activity Index scores, age, race, gender, weight, disease duration and previous antitumor necrosis factor use. Their final analysis was presented at the 2012 Advances in Inflammatory Bowel Diseases Crohn’s & Colitis Foundation’s Clinical & Research Conference.

‘Because we did not see any signal that adalimumab monotherapy increased the incidence of nonmelanoma skin cancer or any other cancers, these results point toward the impact of thiopurines to explain the increased incidence of cancer with combination therapy.’

—James Lewis, MD

The investigators found that 14 of the 694 participants in the analysis who received adalimumab and an immunosuppressant developed a malignancy other than NMSC. This incidence rate was approximately 1.1 malignancies per 100 patient-years— three times higher than the rate of nonNMSC malignancies in the general population (standardized incidence ratio, 3.04; 95% confidence interval [CI], 1.66-5.10). Among those receiving adalimumab with a thiopurine specifically, there was one non-NMSC malignancy per 100 patient-years, translating to a 2.78-fold increase compared with the general population (95% CI, 1.33-5.11).

In separate analyses that looked

41

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Adverse Event Reports Linking Acne Drug To IBD Appear To Be Skewed New Data Show No Causal Link Between Isotretinoin, Risk for IBD

LAS VEGAS— —A recent study suggests that lawyers have been disproportionately reporting cases of inflammatory bowel disease (IBD) triggered by isotretinoin (Accutane, first marketed by HoffmannLa Roche Inc.) to the FDA’s Adverse Event Reporting System (FAERS), especially since the settlement of a landmark case with an extraordinary payout. Furthermore, a separate group of researchers recently published data that “do not suggest an increase in the risk for IBD, including UC [ulcerative colitis] or CD [Crohn’s disease], with use of isotretinoin.” Taken together, the reports dispel the idea that the acne drug somehow causes IBD in patients who have been exposed to the medication.

“The issue is that the link between

specifically at the rates of NMSCs, Dr. Lewis and his colleagues found 1.2 cases per 100 patient-years in those receiving adalimumab with any immunosuppressant, which is 4.59 times higher than what is seen in the general population (95% CI, 2.51-7.70). In the subgroup receiving adalimumab with a thiopurine specifically, they found 1.3 cases of NSMCs per 100 patient-years, translating to a 5.05fold increase compared with the general population (95% CI, 2.61-8.82).

Notably, Dr. Lewis said that when they compared patients who received adalimumab alone with the general population, there were no differences in the rates of any malignancy.

“Because we did not see any signal that adalimumab monotherapy increased the incidence of NMSC or any other cancers, these results point toward the impact of thiopurines to explain the increased incidence of cancer with combination therapy,” he said.

Dr. Long, who was not involved in the study, said that “the sample size was somewhat limited and the risks associated with rarer cancers may not have been detected. Therefore, further data and monitoring are needed as greater numbers of patients are treated with these therapies.”

■ Dr. Lewis has served as a consultant for Abbott. Dr. Long reported no conflicts of interest.

isotretinoin and IBD is association, not causal, and it now appears that the link is being inflated by attorney reporting,” observed William Sandborn, MD, professor of medicine, University of California, San Diego, La Jolla, Calif., who was not involved in either study.

Researchers Take Aim At Lawyer Reporting Having previously demonstrated that lawyers accounted for disproportionate FAERS reports of metoclopramiderelated tardive dyskinesia, researchers at the see Isotretinoin, page 42

All trademarks are owned by Société des Produits Nestlé S.A., Vevey, Switzerland or used with permission. © 2013 Nestlé. All rights reserved. Florham Park, NJ 07932-1521 U.S.A. NEST-12491-0313

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J Pediatr. 1992;120:569-572. 4. Shea JC et al. Pancreatology.

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42

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Isotretinoin continued from page 41

NorthShore University HealthSystem in Evanston, Ill., hypothesized that the same thing might be happening with isotretinoin, an acne drug that has been linked with IBD. “There is some confusion in the literature as to whether this association is true, but there also are many impending lawsuits going on with isotretinoin, specifically with regard to IBD,” said study author Derrick J. Stobaugh, MD, who presented NorthShore’s study at the

annual meeting of the American College of Gastroenterology.

To examine the FAERS reporting patterns of various sources over time, Dr. Stobaugh and his colleagues Parakkal Deepak, MD, and senior author Eli Ehrenpreis, MD, both from NorthShore University HealthSystem, analyzed all reports filed between January 2003 and June 2011, searching for cases of IBD in which isotretinoin, being used as an acne treatment, was the primary suspect.

“The main outcomes we looked for were absolute and relative frequency of

reports by physicians, pharmacists, other health care professionals, consumers and lawyers. In cases of multiple reporters, we chose the physician as the primary one and excluded the secondary to avoid bias and to be more conservative in our methodology,” Dr. Stobaugh said.

They also took into account lawyer reporting of all medications compared with IBD-related isotretinoin, and used the signal inflation factor (SIF) to calculate the degree to which lawyer reports may have distorted the signals of IBD related to isotretinoin. (The World Health

Organization defines a toxic signal as “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously.”)

“An SIF of 2.0 indicates a fair signal distortion, which means that the observed is twice as big as what you would have expected, and ‘expected’ is based on all FAERS,’ ” Dr. Stobaugh explained.

The researchers found that lawyeroriginated reports accounted for only 4% of the 2,562,390 reports filed with FAERS during the 8.5-year period; by comparison, health care professionals accounted for more than half of the reports. However, when it came to the 1,556 reports of isotretinoin-associated IBD, 83% were reported by attorneys.

Of the 1,556 reports of isotretinoin-associated IBD, 83% were reported by attorneys.

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“This is a very stark contrast; we can see here that the driver is clearly lawyers,” Dr. Stobaugh said.

The first large jump in lawyer reporting appeared to occur in response to the first isotretinoin-associated IBD lawsuit filed in July 2003. And the second jump, “a huge jump,” occurred after a landmark case was decided in February 2010 in which the plaintiff was awarded $25 million.

The researchers calculated the SIF to be 4.6.

“This is a clear signal distortion,” Dr. Stobaugh said. “This means the observed is more than four times what we would have expected based on FAERS as a whole. Just to drive this point home, when we compare 2003 with 2010, there is a 0.0% increase in health care professional–originated reporting in the number of cases of isotretinoinassociated IBD, but more than a 3,000% increase with lawyers,” he said.

“To summarize, lawyer-initiated reports are inflating the pharmacovigilance signal of isotretinoin associated with IBD in the FDA’s FAERS. This is a clear distortion based on our data.”

Dr. Stobaugh suggested the absolute and relative contribution of all reporter

43

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2013

sources, including lawyers, should be taken into consideration when reviewing FAERS data.

Dr. Sandborn observed that population-based and caseâ&#x20AC;&#x201C;control data on the risk associated with isotretinoin and IBD were mixed, and trended slightly toward there being no association. â&#x20AC;&#x153;The most interesting study shows a link between oral tetracycline and IBD,â&#x20AC;?

Dr. Sandborn pointed out (Margolis DJ et al. Am J Gastroenteroll 2010;105:26102616). â&#x20AC;&#x153;This study suggests that tetracycline is associated with IBD, which raises the possibility that isotretinoin is just a marker for prior tetracycline use. Anyone who was treated with isotretinoin would almost certainly have had tetracycline first,â&#x20AC;? he noted. â&#x20AC;&#x153;In turn, the association with tetracycline raises the possibility that tetracycline is a marker for acne,â&#x20AC;? Dr. Sandborn added. â&#x20AC;&#x153;So maybe the real association is between IBD and acne.â&#x20AC;?

To this point, Drs. Stobaugh, Deepak and Ehrenpreis published a paper in April addressing the relationship between the use of antibiotics and isotretinoin and

In this study, researchers from the University of British Columbia, Vancouver, Canada, evaluated a cohort of women of reproductive age (18 to 46 years) who had received at least one prescription for an oral contraceptive between May 2001 and December 2009. They identified cases of IBD based on patients having three health care contacts with documentation of IBD, or a single health care contact followed by use of a drug to treat IBD. The investigators identified 20 controls for each case of IBD and calculated risk ratios (RRs) for incident cases of IBD associated with the

use of isotretinoin using incidence-density sampling matched on age and date of diagnosis. They also conducted a meta-analysis of published and unpublished studies on isotretinoin and IBD and estimated a pooled RR using a random-effects model.

In the case-control study, 2,159 cases of IBD (1,056 UC and 1,103 CD) were identified and matched with 43,180 controls. Of these, 10 patients with IBD (0.46%) and 191 controls (0.44%) were exposed to isotretinoin, for an adjusted RR for IBD of 0.99 (95% confidence interval [CI], 0.52-1.90). In the

meta-analysis, the pooled RR for IBD was 0.94 (95% CI, 0.65-1.36).

The investigators concluded that the data do not suggest an increased risk for IBD with isotretinoin use. â&#x20AC;&#x153;Because inflammatory acne in children and adolescents carries a high psychological burden, clinicians should not be discouraged from prescribing this drug owing to a putative association with IBD,â&#x20AC;? the authors wrote. â&#x2013; â&#x20AC;&#x201D;Additional reporting by Cynthia J. Gordon, PhD

New

Leave questions in the past.

â&#x20AC;&#x2DC;Because inflammatory acne in children and adolescents carries a high psychological burden, clinicians should not be discouraged from prescribing this drug owing to a putative association with IBD.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Etminan M et al.

JAMA Dermatol 2013;149:216-220

Get answers as to why response to adalimumab may be lost. Ä&#x2018;ĆŤ 1 *0%Ăź!/ĆŤ3$!0$!.ĆŤ%*Ă˝ )) 0+.5ĆŤ +3!(ĆŤ %/! /!ĆŤ, 0%!*0/ĆŤ ĆŤĆŤĆŤ$ 2!ĆŤ *0% + %!/ĆŤ0+ĆŤ (%)1) ƍĨ ÄŠĆŤ * ÄĽ+.ĆŤ/1Ăž %!*0ĆŤĆŤ ĆŤĆŤĆŤ (%)1) ƍĨ ÄŠĆŤ +* !*0. 0%+*/ĆŤ Ä&#x2018;ĆŤ ! /1.!/ĆŤ ĆŤ%*ĆŤ0$!ĆŤ,.!/!* !ĆŤ+"ĆŤ ĆŤ

the risk for IBD (Eur J Clin Pharmacol 2013;69:1041-1042). In this paper, they reported that concomitant antibiotic usage with isotretinoin treatment for acne does not augment the risk for IBD.

New Data Dispel Isotretinoinâ&#x20AC;&#x201C; IBD Link A recent publication from a different group of researchers found no increased risk for IBD with the use of isotretinoin (Etminan M et al. JAMA Dermatol 2013;149:216-220).

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44

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Electrical Stimulation Demonstrates Encouraging Results In Patients With GERD, Gastroparesis

BY TED BOSWORTH LAS VEGAS—Gastrointestinal (GI) diseases that involve disturbed or inadequate muscle contraction have proven difficult to treat pharmacologically. Now, two separate attempts to employ exogenously delivered electrical stimulation have yielded results sufficiently encouraging that viable clinical devices are in development.

In patients with gastroesophageal reflux disease (GERD), the control of esophageal acid exposure with an implantable device that produces contraction of the lower esophageal sphincter (LES) appears impressive based on 12 months of followup. And in diabetic gastroparesis, a wearable device delivering stimulation to the surface of the skin with a purported effect on motility was able to demonstratte a significant reduction in symptoms relative to a sham device.

Clinic, Hospital Indisa, Santiago, Chile, who performed the surgical procedure in all patients. At the end of 12 months, no patient remained on daily PPI therapy, and 77% of patients reported either normalization or greater than 50% reduction in distal acid exposure over 24 hours. There were no complications related to the implanted device or to the electrical stimulation. No abnormalities of were reported, and no dysphagia was observed on manometry.

“The evidence that the device continues to function after 12 months as it did when first implanted suggests that it is a viable solution for patients who are not adequately controlled on PPIs and want to avoid antireflux surgery,” Dr. Soffer said. In addition to the final one-year results, larger studies now under way will be important to confirming the viability of this therapy.

Gastroparesis

The second evaluation was substantially different in concept, p , even if the ability to use electrrical stimulation to treat aG GI disease was the same.

In n this study, chronic electrical stimulation GERD was delivered to two In studies of electrical stimulaation in acupuncture points patients with GERD, the control off sympthat have previously toms at 12 months was similar to control been associated with EndoStim, a medical device developed to treat gastroat three and six months, which su uggests improving nausea and esophageal reflux disease through electrical stimulation, that electrical stimulation may noot share vomiting. The stimuis not currently approved in the United States. the diminishing benefits associatted lation device, described Images courtesy of EndoStim with previous endoscopic strategiees aas the size of a watch, directed at tightening the LES. was worn on the wrist or w On the basis of objective tests, leg. The leads did not inter“electrical stimulation of the LES fere with daily activities. is associated with normalizaEighteen patients with E tion of both proximal and disdiab betes, all of whom had tal esophageal acid exposure,” refraactory gastroparesis at reported Edy Soffer, MD, directhe time of study enrolltor, GI Motility Program, Unimen nt, served as their own versity of Southern California, conttrols. The crossover Los Angeles. Participating in a desiggn included four weeks ‘Electrical press conference at the annual of electrical stimulation stimulation meeting of the American Coland four weeks of sham lege of Gastroenterology (ACG), stim mulation applied in a of the LES where results of the the pilot stud dy rand dom order. The devices is associated were presented, Dr. Soffer emph haweree worn for two hours with normalization sized that electrical stimulation soo far afterr lunch and dinner. The has not been associated with the side effeccts were evaluated with of both proximal and effects of many of the endoscopic antireflux the nine-question Gastrodistal esophageal devices or with antireflux surgery. pareesis Cardinal Symptom The LES stimulator device, likee a cardiac paceIndeex (GCSI) and the acid exposure.’ maker, is implanted under anesthesia i in i a subcutaneous b 36-question Short Form 36 —Edy Soffer, MD pocket. Two leads are attached to the LES to deliver (SF-36). Each was comelectrical pulses that cause the muscle to contract. In pleted weekly. this study, electrical stimulation was delivered at 20 Hz, quality of life. In the short term of the pilot study, “Five of nine gastroparesis symptoms were improved 215 µs, 3-8 mA in 30-minute sessions timed to coin- improvements in LES pressure and reductions in esoph- over the four weeks that patients used the electrical stimcide with peak periods of reflux events, but the electrical ageal pH tracked with a reduction in GERD symptoms. ulation device,” reported Richard McCallum, MD, propulses can be individualized.

One-year interim results with 23 patients were presented fessor and founding chairman, Department of Medicine, The initial pilot study included 24 patients with at the ACG meeting.

University of Texas Medical Branch, Galveston, who GERD. Most had experienced only a partial response The most notable finding was that all of the effects presented the findings at the ACG meeting. “No signifiwith proton pump inhibitor (PPI) therapy. At baseline, observed at the end of the short term of the pilot study cant improvement was associated with the sham device.” all patients had elevated 24-hour esophageal acid levels, persisted and improved at 12 months, according to The improvements included a 31.1% reduction in as well as impairments in measures of GERD-related Leonardo Rodríguez, MD, of the Obesity and Diabetes see Electrical Stimulation, page 48

LOOKS LIKE HIS DAD.

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HAS IBS LIKE HIS DAD.

TAKES VSL#3 LIKE HIS DAD.1 SURF OVER TO DDW BOOTH #733 TO FIND OUT MORE ABOUT .

For further information call 1-866-GET-VSL3 (438-8753) or visit www.vsl3.com Made in the USA Distributed by Sigma-Tau Pharmaceuticals Inc., Gaithersburg MD © 2013 Sigma-Tau Pharmaceuticals, Inc. All rights reserved.

1

Study Suggests Familial Aggregation of IBS,” MedScape Medical News, December 17, 2003

VSL#3 is a medical food and must be used under medical supervision.

Indication and Important Safety Information Prepopikâ&#x201E;¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM QFSGPSBUJPO UPYJD DPMJUJT PS UPYJD NFHBDPMPO HBTUSJD SFUFOUJPO PS JO QBUJFOUT XJUI B LOPXO BMMFSHZ UP BOZ PG UIF JOHSFEJFOUT JO 1SFQPQJL 1BUJFOUT TIPVME CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH PS TJHOT PG EFIZESBUJPO BGUFS UBLJOH 1SFQPQJL r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT

GPMMPXJOH 1SFQPQJL BENJOJTUSBUJPO 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU

Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a ďŹ&#x201A;exible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t S uperior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 â&#x20AC;&#x201C; 84% vs 74%, respectively, achieving â&#x20AC;&#x153;excellent or goodâ&#x20AC;? visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 *Evaluated in a randomized trial. The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efďŹ cacy endpoint was the proportion of patients with successful colon cleansing deďŹ ned as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1

5P MFBSO NPSF TDBO UIJT DPEF XJUI ZPVS TNBSUQIPOF PS HP UP XXX QSFQPQJL DPN

Reference: 1. Prepopikâ&#x201E;˘ Prescribing Information, July 2012.

Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

PREPOPIKTM is a trademark of Ferring B.V. Š 2013 Ferring B.V. All rights reserved.

PK/047/2013/USa

48

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2013

Researchers Tout Efficacy and Safety of NOTES Procedure in the Treatment of Achalasia â&#x20AC;&#x2DC;Outstandingâ&#x20AC;&#x2122; Results, Despite â&#x20AC;&#x2DC;Incredibly Shortâ&#x20AC;&#x2122; Follow-Up Period

BY DAVID WILD LAS VEGASâ&#x20AC;&#x201D;Endoscopic myotomy is a safe and effective noninvasive treatment for achalasia, according to recent data.

Researchers showed that 94% of patients

with achalasia who were treated with peroral endoscopic myotomy (POEM) experienced significant improvements, without significant complications. â&#x20AC;&#x153;This may be the first NOTES [natural orifice transluminal endoscopic surgery] procedure to replace a traditional

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Not for Direct Ingestion (DFK SDFNHW PXVW EH GLVVROYHG LQ RXQFHV RI FROG ZDWHU DQG administered at separate times according to the dosing regimen.

The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information.

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laparoscopic surgeryâ&#x20AC;&#x201D;the Heller myotomyâ&#x20AC;&#x201D;by offering at least the same efficacy and risk profile via a much less invasive approach,â&#x20AC;? said lead researcher Stavros Stavropoulos, MD, director of endoscopy in the Department of Gastroenterology, Hepatology and Nutrition at Winthrop

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University Hospital in Mineola, N.Y. Dr. Stavropoulos and his colleagues were the first to perform POEM outside Japan, where the procedure was pioneered.

Since their first procedure in 2009, they have accrued three-month follow-up data in achalasia patients treated with the procedure. They presented the data at the American College of Gastroenterologyâ&#x20AC;&#x2122;s Annual Scientific Meeting, and recently published data on the current worldwide experience with endoscopic treatment, including POEM, for achalasia (Stavropoulos SN et al. Therap Adv Gastroenterol 2013;6:115-135).

Summarizing his teamâ&#x20AC;&#x2122;s experience of treating 37 patients with achalasia, Dr. Stavropoulos said that most patients had non-sigmoid esophageal dilation. Preprocedure esophageal dilations had a mean of 5.1 cm (range, 2.1-11 cm). Thirty-five percent of the patients, who had a mean age of 52 years at the time of treatment, had failed prior therapies, including botulinum toxin injection, pneumatic dilation or laparoscopic Heller myotomy.

Dr. Stavropoulos reported that Eckardt Scoresâ&#x20AC;&#x201D;an index combining measures of dysphagia frequency, regurgitation, chest pain and the extent of weight lossâ&#x20AC;&#x201D; dropped from a mean of 7.8 at baseline to 0.4 at three months after the procedure (P<0.0001). The mean value for lower esophageal sphincter (LES) pressure decreased from 45 mm Hg at baseline to 15.2 mm Hg at follow-up (P<0.0001).

Electrical Stimulation continued from page 44

retching (P=0.006), P a 29.7% reduction in nausea (P=0.005), P a 21.4% reduction in the sensation of abdominal fullness (P=0.0047) P and a 20.6% reduction in bloating (P=0.006).

P The study is small, but the controlled nature of the trial strengthens the evidence that this home-based, non-invasive method of electrical stimulation may be an effective strategy for treating gastroparesis. While strengthened muscle contraction is one of the potential benefits, Dr. McCallum suggested that these effects were mediated through increased vagal nerve activity improving central control of nausea and vomiting as well as enhancing gastric motility.

Asked to comment about the potential of electrical stimulation, Joel E. Richter, MD, director, Division of Digestive

49

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

‘This may be the first NOTES procedure to replace a traditional laparoscopic surgery—the Heller myotomy—by offering at least the same efficacy and risk profile via a much less invasive approach.’

—Stavros Stavropoulos, MD

Dr. Stavropoulos said that two patients had recurrent symptoms following the procedure, although both responded well to subsequent pneumatic dilation. There were no significant complications and most patients did not require post-procedure analgesia.

All of the procedures were performed by a gastroenterologist and were 145 minutes long, on average (range, 43-240 minutes).

The mean length of myotomy was 8.6 cm (range, 3-14 cm) and patients required a mean 2.2 days of hospital stay following the POEM procedure (range, one to five days).

Marco Patti, MD, professor of surgery and director of the Center for Esophageal Diseases at the University of Chicago Pritzker School of Medicine, showed tempered enthusiasm regarding the study’s results, noting that “the follow-up period was incredibly short” and that long-term durability is a requirement before the procedure can be considered effective.

“Furthermore, the average post-procedure LES pressure is too high, given that data suggest an LES pressure less than 10 mm Hg is needed in order to avoid recurrent symptoms,” Dr. Patti noted.

While agreeing with Dr. Patti that long-term follow-up data are needed to draw firm conclusions about the procedure, Irving Waxman, MD, professor of medicine and surgery, and director of the Center for Endoscopic Research and Therapeutics, also at the University of Chicago Pritzker School of Medicine, said the study findings are “outstanding and, at face value, POEM achieved the same results as surgical achalasia treatments.”

However, he also wondered whether POEM “will ever be mainstream and

whether gastroenterologists will be performing it.

“I do think it’s a very promising procedure and that we’ll see tertiary care centers offering it, but there are a couple of potential barriers to POEM being adopted by gastroenterologists,” Dr. Waxman noted. “Namely, it requires advanced skill in therapeutic endoscopy and endoluminal resection techniques and a significant volume of procedures need to be conducted to become adept at it, which is difficult, given that achalasia is not a rampant disease.”

■

Expanding the Scope of GI Education

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Diseases and Nutrition, University of South Florida, Tampa, expressed some enthusiasm.

“This device is exciting because it is easy to place and does not require dissection of the hiatus and no fundoplication, so side effects should be rare.”

Although Dr. Richter emphasized that longer and larger studies are clearly needed to confirm the viability of this approach, he said that the increase in LES pressure suggests that this is “truly an anti-reflux treatment.” He also was impressed by the adjustable features of the device.

“Since the power setting and timing of stimulation can be individualized for each patient’s lifestyle, this technology may offer the first personalized treatment for GERD,” Dr. Richter said.

■

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50

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

PPI-Responsive Esophageal Eosinophilia Appears To Deserve Its Own Clinical Subcategory

BY TED BOSWORTH LAS VEGAS— —A prospective study has reinforced previously reported empirical observations that a proton pump inhibitor (PPI) trial is a valuable strategy for both treatat ing and subtyping patients with esophageal eosinophili philia (EoE). Based on the findings, the authors suggeste sted that PPI-responsive EoE (PPI-REE) deserve ves attention as an independent clinical entity, eveen if the precise pathophysiology remains uncleear.

PPI-REE may not just represent missed cases of gastroesophageal reflux disease (GERD).

“My personal sense is that some proportion of the PPI-REE population has true EoE but is responding to this anti-inflammatory property of PPIs,” reported Evan S. Dellon, MD, MPH, of the Division of Gastroenterology, University of North Carolina, Chapel Hill, who presented the study att the annual meeting of the American Collegee of Gastroenterology (ACG). Dr. Dellon wass referring to a series of recent studies generat-ing “increasingly compelling” evidence thatt PPIs may directly or indirectly modify eosinophil migration to the esophagus.

In this study, esophageal biopsies were taken from 173 consecutive patients with dysphagia referred for upper endoscopy. Of these, 65 patients had EoE on the basis of >15 eosinophils per high power field (HPF) as read by a blinded pathologist. These individuals were initiated on twice-daily PPI for eight weeks before undergoing a second upper endoscopy and biopsy. Patients were considered to have PPI-REE if they had a symptomatic and histologic (<15 eosinophils/HPF) response.

Of those with EoE on the basis of the first biopsy, 41 patients (63%) retained this diagnosis at the end of PPI treatment. In these patients, symptoms were not controlled, and the second biopsy again showed >15 eosinophils per HPF. The remaining 24 (37%) had both a symptomatic and histologic response (<15 eosinophils per HPF) to the PPI, fulfilling the study definition of PPI-REE. When compared, PPI-REE patients were, on average, significantly older (48 vs. 36 years; P<0.001), more likely to have erosive esophagitis (21% vs. 5%; P P=0.02), more likely to have Schatzki’s ring (21% vs. 2%; P P=0.04) and

Liver Stiffness continued from page 13

a fasting period of 120 minutes before undergoing TE to measure liver stiffness.

During the past decade, TE has become an important tool for assessment of fibrotic evolution in chronic liver disease. TE has been shown to discriminate between at least three areas of fibrotic evaluation and can reduce the number of liver biopsies necessary for patient management. However, there is no

more likely to be male (88% vs. 63%; P<0.05). Additionally, PPI-REE patients were significantly less likely (all P<0.05) to have esophageal rings (63% vs. 90%), diffuse narrowing (8% vs. 42%), linear furrows (58% vs. 88%) and decreased vascularity (0% vs. 32%).

‘In some cases, PPIresponsive EoE may be a missed case of GERD, but these data suggest that something else is going on.’

—Evan S. Dellon, MD, MPH

These differences support the likelihood that PPIREE is a distinct phenotype from EoE. Although Dr. Dellon acknowledged that the overlap of these features is considerable and that he is often confounded by patients who respond to PPIs despite features more closely associated with PPI-unresponsive EoE, he believes that the results of this study support the concept that they should be managed differently.

“In some cases, PPI-REE may be a missed case of GERD, but these data suggest that something else is going on.”

In fact, Dr. Dellon believes that the anti-acid effect of PPIs may not explain the benefit in patients with PPI-REE. He has been impressed with recent evidence that some of the effects of PPIs in patients with EoE may be mediated by anti-inflammatory activity. Of several recent papers that Dr. Dellon said have associated PPIs with anti-inflammatory activity, he cited a study in which omeprazole blocked expression of eotaxin-3, a

precise recommendation on fasting before TE testing. Investigators said that without an understanding of the effects of meal consumption on the tests, many patients might receive inaccurate results.

Ultrasonic elastography is currently under evaluation by the FDA, said Nezam H. Afdhal, MD, chief of hepatology and director of the Liver Center at Beth Israel Deaconess Medical Center, Boston. “With that in mind, this is an important paper because it shows the importance of

promoter of eosinophil upregulation (Cheng E et al. Gut 2012 May 12. [Epub ahead of print]).

Regardless of the mechanisms, several other studies, including another prospective study conducted in Europe, also have demonstrated a substantial rate of response from PPI therapy in patients with EoE, according to Dr. Dellon. Although this study encourages furD tther research to understand how PPI-REE is best defined and how it differs mechanistically b from EoE not responsive to PPIs, Dr. Dellon suggested that the results do underscore “the iimportance of a PPI trial in the diagnostic allgorithm for EoE.” Asked to comment on these findings, Stuaart Spechler, MD, chief of gastroenterology at tthe Dallas VA Medical Center, accepted PPIREE as a useful empirical subgroup of EoE. R He said he also has been impressed by the evidence that PPIs appear to have “a number of potential anti-inflammatory effects that have nothing to do with their effects on gastric acid secretion.” Although a trial of PPI therapy was ttraditionally recommended for patients with esophageal symptoms and eosinophilia in order to distinguish EoE from GERD, he indicated that this orientation is changing.

“The recent demonstration by Cheng et al. that PPIs block Th2 cytokine-stimulated eotaxin-3 expression by esophageal epithelial cells is one of those acid-independent PPI effects that might explain some cases of PPI-REE,” observed Dr. Spechler, who has published frequently on the topic of EoE. Although “the interaction between GERD and esophageal eosinophilia remains a confusing and fascinating issue,” he suggested that an anti-inflammatory effect from PPIs may provide one piece of the puzzle.

“I suspect that PPI-REE is not one disease, but rather a heterogeneous group of disorders in which some patients respond to the well-known anti-secretory effects of PPIs while others respond to the lesser-known anti-inflammatory effects,” Dr. Spechler noted.

“In the next few years, ongoing research in this area should shed much light on the mechanisms underlying PPI-REE.” ■

doing it in a fasting fashion because the relative changes that take place can be significant.”

Dr. Afdhal added that food consumption joins a list of other potential confounders for elastography, including inflammation, right heart failure and jaundice.

Guadalupe Garcia-Tsao, MD, professor of medicine (digestive diseases) at Yale School of Medicine in New Haven, Conn., said the study will have implications for researchers in the United States who are looking

Drs. Dellon and Spechler reported no potential conflicts of interest.

at different forms of elastography and for clinicians throughout the rest of the world.

“We don’t know how many patients would be misclassified because of food consumption but certainly there is the potential. We need to be mindful of these changes and ask the patients to fast at least two hours before you do the study,” Dr. Garcia-Tsao said.

Using TE to measure liver stiffness is not currently approved in the United States but is increasingly used in both Europe and Asia.

■

For the treatment of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF) or other conditions

ULTRESA™ helps treat malabsorption* and stool symptoms 1-2 of EPI

Important Safety Information Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement. Exercise caution when doses of ULTRESA exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) To avoid irritation of oral mucosa, do not chew ULTRESA or retain in mouth Exercise caution when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia There is theoretical risk of viral transmission with all pancreatic enzyme products, including ULTRESA In rare cases, patients taking pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase) have experienced severe allergic reactions including anaphylaxis, asthma, hives, and pruritus

The most common adverse reactions (*7% of patients treated with ULTRESA) were headache, pharyngolaryngeal pain, and epistaxis Use of ULTRESA in pediatric patients is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight ULTRESA is not interchangeable with any other pancrelipase product *Reduction in malabsorption is shown by improvement in coefficient of fat absorption (CFA), primary endpoint, and coefficient of nitrogen absorption (CNA), secondary endpoint.1-2 References: 1. Konstan MW, Liou TG, Strausbaugh SD, et al. Efficacy fi and safety of a new formulation of pancrelipase (Ultrase MT20) in the treatment of malabsorption in exocrine pancreatic insufficiency fi in cystic fibrosis. Gastroenterol Res Pract. 2010.

2. Data on file (UMT20CF05-01), Aptalis Pharma US, Inc., Bridgewater, NJ.

Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin Please read brief summary of full US Prescribing Information on following pages. © 2012 Aptalis Pharma US, Inc., Bridgewater, NJ.

All rights reserved.

Printed in USA.

UL227-0912b

ULTRESA (pancrelipase) delayed-release capsules, for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR ULTRESA (pancrelipase) delayed-release capsules: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE ULTRESA™ (pancrelipase) is a combination of porcine-derived lipases, proteases, and amylases indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions.

2 DOSAGE AND ADMINISTRATION ULTRESA is not interchangeable with other pancrelipase products.

ULTRESA is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of ULTRESA should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

2.1 Administration Children and Adults ULTRESA should be taken during meals or snacks, with sufficient fluid. ULTRESA capsules should be swallowed whole. ULTRESA capsules p and capsule p contents should not be crushed or chewed.

For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents sprinkled on a small amount of applesauce, yogurt and other acidic soft food with a pH of 4.5 or less at room temperature.

The ULTRESA-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth to avoid mucosal irritation.

Any unused portion of capsule contents should be discarded, and not used for subsequent dosing. The remaining exposed contents may lose potency and become less effective.

2.2 Dosage Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences. ULTRESA should be administered in a manner consistent with the recommendations of the Conferences provided in the following paragraphs. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.

Children Older than 12 Months and Younger g than 4 Years and Weight g 14 kgg or Greater Children older than 12 months and younger than 4 years, weighing under 14 kg should not be dosed with this product because capsule dosage strengths cannot adequately provide dosing for these children.

Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Children 4 Years and Older and Weight g 28 kgg or Greater and Adults Children 4 years and older, weighing under 28 kg should not be dosed with this product because capsule dosage strengths cannot adequately provide dosing for these children.

Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Usually, half of the prescribed ULTRESA dose for an individualized full meal should be given with each snack. The total daily dosage should reflect approximately three meals plus two or three snacks per day.

Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.

Limitations on Dosing: g Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines. If symptoms and signs of steatorrhea persist, the dosage may be increased by a healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)].

Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

Use of ULTRESA in children is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight. Attempting to divide the capsule contents in small fractions to deliver small doses of lipase is not recommended.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products.

Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually with use over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age. Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. It is generally

recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.2)].

Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

5.2 Potential for Irritation to Oral Mucosa Care should be taken to ensure that no drug is retained in the mouth. ULTRESA should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and Administration (2.1) and Patient Counseling Information (17.1) in the full prescribing information] For patients who are unable to swallow intact capsules, the contents may be sprinkled on applesauce, yogurt and other acidic soft food with pH 4.5 or less. The ULTRESA-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion.

5.3 Potential for Risk of Hyperuricemia Caution should be exercised when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.

5.4 Potential for Viral Exposure from the Product Source ULTRESA is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that ULTRESA will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.

5.5 Allergic Reactions Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued ULTRESA treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.

6 ADVERSE REACTIONS The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions (5.1, 5.3 and 5.5)].

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The short-term safety of ULTRESA was assessed in two clinical trials conducted in 40 patients with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). Study 1 was conducted in 31 patients, ages 8 years to 37 years; Study 2 was conducted in 9 patients, ages 7 years to 11 years.

Study 1 was a randomized, double-blind, placebo-controlled, crossover study of 31 patients, ages 8 to 37 years, with EPI due to CF. In this study, patients were randomized to receive ULTRESA at doses not to exceed 2,500 lipase units per kilogram per meal or matching placebo for 6 to 7 days of treatment, followed by crossover to the alternate treatment for an additional 6 to 7 days. The mean daily dose of ULTRESA was 6,270 lipase units per kilogram body weight per day. The mean exposure to ULTRESA during this study was 5.4 days.

The most common adverse reactions (≥7%) were headache, pharyngolaryngeal pain, and epistaxis.

Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 7%) treated with ULTRESA at a higher rate than with placebo in Study 1.

TABLE 1 Adverse Reactions Occurring in at Least 2 Patients (≥ 7%) in Cystic Fibrosis (Study 1) ULTRESA n=30 n (%)

PLACEBO n=31 n (%)

Headache

2 (7%)

1 (3%)

Pharyngolaryngeal Pain

2 (7%)

1 (3%)

Epistaxis

2 (7%)

0

Adverse Reaction

Study 2 was an open-label study of 9 patients, ages 7 years to 11 years, with EPI due to CF. After a screening period of up to 15 days on individually-titrated doses of ULTRESA not to exceed 2,500 lipase units per kilogram per meal, patients entered a washout phase (no treatment) of up to 7 days before returning to a treatment phase of up to 12 days on the same individually-titrated dose of ULTRESA. Two patients discontinued during the washout phase leaving 7 patients in the treatment phase. The mean daily dose of ULTRESA was 6,361 lipase units per kilogram body weight per day during the last 4 days of the screening phase, and was 6,846 lipase units per kilogram body weight per day during the treatment phase. The mean duration of the treatment phase was 5.7 days.

Adverse reactions that occurred during treatment with ULTRESA were nasal congestion (14%), neck pain (14%), beta-hemolytic streptococcal infection (11%), ear pain (11%), and lymphadenopathy (11%).

6.2 Postmarketing Experience Postmarketing data for ULTRESA has been available since 2003. The safety data is similar to that described below. Because these reactions are reported voluntarily from a population of uncertain size,

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

53

Possible Increased Risk for Pancreatitis, Precancerous Findings With Use of Some Diabetes Drugs, FDA Says The FDA is evaluating new findings that suggest an increased risk for pancreatitis and pancreatic duct metaplasia in patients with type 2 diabetes being treated with incretin mimetics.

Drugs that fall under this category include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni) and linagliptin (Tradjenta, Jentadueto). These drugs work by mimicking the naturally occurring incretin hormone that stimulates the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar levels in adults with type 2 diabetes.

With regard to incretin mimetics, the warnings and precautions section of drug labels and patient medication guidelines contain warnings about the risk for acute pancreatitis, but the FDA has not communicated previously the potential risk for precancerous findings.

The current investigation is being undertaken in response to the unpublished findings of a group of academic researchers who examined a small

number of pancreatic tissue specimens taken from patients after they had died from unspecified causes. The FDA has asked the researchers to provide the methodology they used to collect

‘Patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.’

it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Pancreatic enzyme products (delayed and immediate-release) with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse events included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of preexisting carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. The most commonly reported adverse events were gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and nausea, and skin disorders including pruritus, urticaria and rash.

7 DRUG INTERACTIONS No drug interactions have been identified. No formal interaction studies have been conducted.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic g effects Pregnancy Category C. Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ULTRESA should be given to a pregnant woman only if clearly needed.

The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULTRESA is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.

8.4 Pediatric Use The short-term safety and efficacy of ULTRESA were assessed in two clinical studies in pediatric patients with exocrine pancreatic insufficiency due to cystic fibrosis; one study included patients aged 8 years to 17 years, and the other included patients aged 7 years to 11 years.

Study 1 was a randomized, double-blind, placebo-controlled crossover study of 31 patients with exocrine pancreatic insufficiency due to cystic fibrosis including 2 children aged 8 to 11 years, and 12 adolescents aged 12 to 17 years. The safety and efficacy in pediatric patients in this study were similar to that in adult patients [see Adverse Reactions (6.1) and Clinical Studies (14) in the full prescribing information].

Study 2 was an open-label study of 9 pediatric patients, ages 7 years to 11 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Patients showed similar control of fat malabsorption as in the treatment arm of Study 1 [see Adverse Reactions (6.1) and Clinical Studies (14) in the full prescribing information].

—FDA press release

and study these specimens and also to provide the tissue samples so the agency can further investigate the potential toxicity associated with incretin mimetics.

At press time, the FDA had not reached any new conclusions about the safety risks associated with incretin mimetics. The agency plans to participate in the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute’s Pancreatitis Diabetes Pancreatic Cancer Workshop in June to gather and share additional information (www2. niddk.nih.gov/News/Calendar/PDPC2013.htm).

The FDA plans to communicate its final conclusions and recommendations when its review is complete, or when it has additional information to report.

The FDA stated that “patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.”

—Based on a press release from the FDA

The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.

Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences. However, use of ULTRESA in children is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight.

Attempting to divide the capsule contents in small fractions to deliver small doses of lipase is not recommended [see Dosage and Administration (2)]. Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age [see Warnings and Precautions (5.1)].

8.5 Geriatric Use Clinical studies of ULTRESA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE There have been no reports of overdose in clinical trials or postmarketing surveillance with ULTRESA. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Dosage and Administration (2) and Warnings and Precautions (5.1)]. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.

Marketed by: Aptalis Pharma US, Inc. 22 Inverness Center Parkway Birmingham, AL 35242 USA Manufactured by: Aptalis Pharma S.r.L. Pessano, Italy 20060 ULTRESA and APTALIS are trademarks. © 2012 APTALIS PHARMA US, INC.

54

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2013

FDA Approves First-in-Class Drug, Invokana, To Treat Type 2 Diabetes On March 29, the FDA approved Invokana (canagliflozin) tablets, for use with diet and exercise, to improve glycemic control in adults with type 2 diabetes.

Invokana works by blocking the reabsorption of glucose by the kidney, increasing glucose excretion and lowering the levels of blood glucose in people with diabetes in whom these levels are high. Its safety and efficacy were evaluated in nine

clinical trials involving more than 10,285 patients with type 2 diabetes.

Trial results showed improvement in hemoglobin A1c and fasting plasma glucose levels. â&#x20AC;&#x153;Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose cotransporter 2 [SGLT2] inhibitors,â&#x20AC;? said Mary Parks, MD, director of the Division of Metabolism and Endocrine Products in the FDAâ&#x20AC;&#x2122;s Center

for Drug Evaluation and Research.

The FDA is requiring five postmarketing studies for Invokanaâ&#x20AC;&#x201D;a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the Pediatric Research

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Equity Act, including a pharmacokinetic and pharmacodynamic study and a safety and efficacy study.

Invokana has been studied as a stand-alone therapy and in combination with other therapies for type 2 diabetes, including metformin, sulfonylurea, pioglitazone and insulin.

Invokana should not be used to treat people with type 1 diabetes; those who have increased ketones in their blood or urine; or those with severe renal impairment, end-stage renal disease or in patients on dialysis.

For more information about Invokana, manufactured by Janssen, visit www.invokanahcp.com. â&#x20AC;&#x201D;Based on a press release from the FDA

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

55

FDA Approves Delzicol for the Treatment of Ulcerative Colitis Delzicol (Mesalamine) Capsules To Replace Asacol Tablets Warner Chilcott recently announced that the FDA has approved its new product, Delzicol (mesalamine), for the treatment of mildly to moderately active ulcerative colitis (UC) and for the maintenance of remission of UC.

pain, diarrhea, constipation, headache, back pain, tiredness, vomiting and fever. Reports of liver failure also have been associated with mesalamine-containing products like Delzicol in patients who have or have had liver disease, according to the safety information issued by Warner Chilcott. Mesalamine also may increase the risk for kidney

problems when used with nonsteroidal anti-inflammatory drugs and may increase the risk for blood disorders when used with azathioprine and 6-mercaptopurine.

For the treatment of adults with mildly to moderately active UC, the recommended dose of Delzicol is two 400-mg capsules taken three times daily (2.4 g total daily dosing).

To maintain remission of UC, the recommended dosage for adults is 1.6 g daily, in divided doses. The medication should be swallowed whole and taken at least one hour before a meal or two hours after, according to the manufacturer’s prescribing information.

—Based on a press release from Warner Chilcott

Simple

Easy to learn, implement, and use.

Delzicol, a delayed-release 400-mg capsule, contains the same active ingredient and works in the same way as Asacol, which also is indicated for the treatment and maintenance of remission of UC. Delzicol offers the same efficacy and safety profile as Asacol, but comes in a capsule formulation. (Asacol was formulated as a tablet but is no longer being manufactured, according to the product website.)

According to the Delzicol website, “patients (N=331) preferred capsules versus coated and uncoated tablets of the same size and shape; capsules were also perceived as easier to swallow compared to tablets” (www. delzicol.com/index.jsp#Indication).

Common adverse effects associated with Delzicol include stomach

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

FDA Issues Clearance for invendo medical’s Single-Use Colonoscopy System In February, invendo medical announced that it received 510(k) clearance from the FDA for its new C20 colonoscopy system including the SC20 single-use colonoscope.

“We are extremely excited to be bringing this new colonoscopy system to the U.S. market,” said Berthold Hackl, CEO of the company.

“We believe that the invendo system reduces the burden associated with current conventional systems and that it may help to improve colonoscopy compliance rates, one of the key factors affecting the future incidence of colorectal cancer.”

The invendoscope SC20 has several features that are new to the field of colonoscopy: a singleuse colonoscope with a working channel, computer-assisted gentle drive technology that eliminates the need for manual push or pull, and a handheld device with which all endoscopic functions are performed. The new system was first installed in NewYork-Presbyterian Hospital/Columbia University Medical Center and NYU Langone Medical Center, both in New York City.

Results from a clinical trial showed a cecal intubation rate of 98% or better and a 41% rate of detection of lesions in screening subjects, according to invendo. No device-related adverse events were observed during the study.

Based in Garden City, N.Y., and Kissing, Germany, invendo medical

invendo medical’s SC20 single-use colonoscope

All endoscopic functions of the invendoscope SC20 are performed using a handheld device.

SC20 single-use colonoscope, deflection

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develops disposable endoscopy products in the field of gastroenterology. For more information, visit www.invendo-medical.com.

—Based on a press release from invendo medical

SC20 single-use colonoscope, tip

FDA Issues 510(k) Clearance for Articulating HD 3D Laparoscopic Surgical Video System From Olympus Olympus has received 510(k) clearance from the FDA for its Articulating HD [high-definition] 3D [three-dimensional] Laparoscopic Surgical Video System.

According to Olympus, its Articulating HD 3D Laparoscopic Surgical Video System reduces surgical errors and improves the speed, accuracy and precision of surgical tasks such as dissection, grasping and suturing when compared with traditional twodimensional surgical systems. This is accomplished by restoring natural 3D vision and depth perception during the performance of laparoscopic procedures and is independent of a surgeon’s skill level, the company said.

“The Olympus HD 3D system is ideal for suturing, accurately identifying tissue planes, and other precision surgical tasks that are required in my laparoscopic surgical cases,” said Marcos Michelotti, MD, assistant professor of surgery at Loma Linda University Health System, Loma Linda, Calif., in a press release from Olympus. “In addition, the articulating design enables me to obtain the critical view of anatomical structures in HD 3D without losing the important visual horizon. This is not possible with traditional, fixed-angle laparoscopes.”

The Olympus video platform is available as a module that can be

The ENDOEYE FLEX 3D from Olympus, the world’s only Articulating HD 3D Video laparoscope.

Photo courtesy of Olympus

added to an existing Olympus EVIS EXERA III Universal Imaging System. This modular design reduces the investment necessary to add 3D capability and allows surgeons to choose either 2D or 3D visualization from the surgical field.

“The Olympus HD 3D system brings value to those surgeons that need the precision, resolution and depth perception of 3D without the substantial capital investment and annual maintenance expenses associated with alternatives such as robotic technology,” said Luke Calcraft, president, Medical Systems Group, Olympus Corporation of the Americas.

“We are leading the way with innovations to help our customers realize the clinical efficacy and cost-effectiveness required under Accountable Care,” he added.

—Based on a press release from Olympus

All photos courtesy of invendo medical

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Another Successful Year For the McMahon Group

2012

to recognize the best of an outstanding group of empployees. Now into its fifth decade, the company continues to publish best-read medical newspapers and must-view meddical websites covering several clinical areas, and also creates medical education platforms for physicians, nurses andd pharmacists.

All of which proves yet again that a company pow powered wered by talented people will necessarily generate su success. uccess

Here is a review of the winners of the 2012 employee awards: MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

Each year employees are asked to select two outstanding mem mbers representing these diverse departments. The first winner was DIANE LODISE, who is both the director of facilities managemeent, overseeing the facilities owned by the company, and the conveentions coordinator, planning the many details of our extensive convenntion coverage.

The second winner was HYON NG KWON, the company’s development manager for IT, for his continuuing efforts in improving the company’s digital presence.

MAX GRAPHICS PERSON OF THE YEAR

MOST IMPROVED SALESPERSON OF THE YEAR

BLAKE DENNIS was recognized for her excellence as art directtor for Anesthesiology News as well as her graphic design of a varietyy of special projects. Blake is dedicated to creating the most visually appeaaling projects possible.

BRIAN HIGGINSON, publicatioon director for Gastroenterology & Endoscopy News, was recogniized for the increase in that publication’s sales in 2012, which in part ledd to one of its most profitable years ever.

His dedication to his clients’ needs and understanding of their products ensure his continued success in sales.

ASSOCIATE/SENIOR/PROJECTS EDITOR OF THE YEAR

MANAGING EDITOR OF THE YEAR

Editorial director of the special projects division, division KATHERINE REIDER was recognized for her contributions as an editor and for providingg leadership and direction to the members of the department. Her diplomacy skills and focus on process have helped ensure that projects are devveloped with the highest level of accuracy and in a timely manner. Katherinee also was recognized for her 10 years of service at McMahon.

GEORGE OCHOA was voted ed editor of the year for his efforts and dedication to McMahon Groupp through his exemplary writing and editing.

His stories appear in every McMahon Group publication and on every website and provide the manaaging editors with articles that exemplify editorial excellence.

SALES ACHIEVEMENT AWARD

SALESPERSON OF THE YEAR

The publication director for General Surgery News, MICHAEL ENRIGHT, T was selected for this award in recognition of his strong commitment to his clients and his innovative thinking to create unique marketing platforms, which included the publication’s first international edition as well as the initiation of a website video arcade.

For an unprecedented seventhh year in a row, RICHARD TUORTO earned the salesperson of the year aw ward. Unlike the other awards, which are decided by peer votes, this aw ward is presented to the individual who brings in the most revenue in the calendar year. Richard manages the Anesthesiology News and Painn Medicine News teams as senior group publication director.

THE MCMAHON GROUP PERSON OF THE YEAR

PARTNERS’ AWARD

The top award each year is for the person of the year, which gooes to the employee who goes above and beyond the call throughout thee year.

JEANNIE MOYER, associate director of human resources, received the honor this year. Jeannie oversees personnel and works tirelessly to provide the best possible atmosphere for employees each day. She is integral to helping McMahon Group continue to grow every year.

From time to time, the partner--owners of the company recognize the contributions of those who havee had a significant effect on the company’s success through the years. The 22012 award was given to WARD BYRNE, who served as publication director foor Anesthesiology Newss for several years, starting in the early 1990s. He w was responsible for the excellent growth of that newspaper, which today dominates the market. Ward eventually left McMahon Group to start what would be ann 11-year career working at a medical education company, after which he returneed to his true love — teaching. Today, Ward teaches special education in thee New Jersey school system.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

F D A U P D AT E & P R O D U C T N E W S

59

gMed Launches New Iteration of EHR System for Gastroenterologists The specialty electronic health record (EHR) company gMed has launched a new version of its EHR system software gGastro+. The new software is designed specifically for gastroenterology practices, ambulatory surgery centers and endoscopy centers.

Highlights of gGastro+ include “gScheduler,” “Online Bill Pay” and the “Patient Recalls” modules. Its “Patient Portal” feature meets HIPAA requirements and allows patients to schedule and check appointments, receive test results and check prescription information online. Other functionalities of the software include an image management system that acquires images in real time directly from any video endoscope, a

laboratory results management system, an order tracking system and advanced procedure reporting. gGastro+ is certified for Meaningful Use, the Centers for Medicare & Medicaid Services program that offers a financial incentive to health care providers who use certified EHR technology in a way that provides optimal patient care. It also is certified to submit data to the GI Quality Consortium, a quality reporting

initiative of the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy. Additionally, gGastro+ is approved to connect directly to the Digestive Health Outcomes registry of the American Gastroenterological Association.

For more information, visit www. gmed.com.

—Based on a press release from gMed

Good for your Patients. Great for your Practice.

QuinTron’s BreathTracker™ Analyzer For Breath Hydrogen & Methane Testing Has Evolved With New Advanced Features

THE BREATHTRACKER T PROVIDES: NOW PROVIDES Increased Throughput— Increased Throughput 2x faster than previous model

“We are very happy to be launching gGastro+, the only product in the industry that offers a fully integrated platform that includes an electronic health record, practice management, endoscopy report writer and patient portal built for gastroenterologists,” said Samuel Rubinsztain, vice president of product management at gMed, in a statement.

“With gGastro+, gastroenterology practices will be able to decrease costs and create efficiencies not previously available to them. Staff members now have access to clinical and financial data at their fingertips, allowing them to provide better care anytime they provide services to their patients. It’s truly a game changer,” Mr. Rubinsztain said.

Gastroenterology & Endoscopy News’

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Simple breath-testing kits for SIBO as well as Lactose & Fructose Malabsorption coupled with QuinTron’s BreathTracker can increase your ROI and improve quality of life for your patients suff fferingg from IBS.

Patients and your practice benefit fi from industry-leading features that have established QuinTron’s analyzers and breath collection kits as simple, accurate and reliable since 1962.

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F D A U P D AT E & P R O D U C T N E W S

FDA Approves Test To Evaluate Patient Response To Hepatitis C Therapy The FDA has approved a next-generation viral-load test from Roche to be used in the management of patients with chronic hepatitis C virus (HCV) infection. The COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test (version 2.0) uses a dual-probe approach and is designed to accurately quantitate HCV RNA levels in order to assess a patient’s response to antiviral therapy.

management of patients with chronic HCV infection, in conjunction with clinical and laboratory markers of infection. It is an in vitro nucleic acid amplification test for the quantitation of HCV RNA genotypes 1 to 6 in human plasma or serum. The test can be used to predict the probability of sustained virologic response (SVR) early during a course of antiviral therapy, and to assess

The COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test (version 2.0) from Roche Photo courtesy of Roche

“The rapidly changing hepatitis C treatment landscape requires tests with an additional layer of protection in detecting and accurately quantifying hepatitis C RNA across genotypes,” said Roland Diggelmann, chief operating officer of Roche’s Diagnostic Division. “This test can play a valuable role in response-guided therapy, helping physicians and patients to better manage the disease and optimize treatment choices and duration.”

The COBAS AmpliPrep/COBAS TaqMan HCV Test is intended for use in the

response to antiviral treatment as measured by changes in HCV RNA level.

This real-time PCR-based HCV test is designed for use with Roche’s fully automated COBAS AmpliPrep/COBAS TaqMan system, an established platform for viral-load monitoring of multiple infectious diseases that improves workflow in testing laboratories. The system can be combined with the COBAS P630 instrument that provides an integrated, preanalytical primary tube-handling solution.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

Gilead Submits New Drug Application for HCV Polymerase Inhibitor, Sofosbuvir Gilead Sciences recently announced that it has submitted a New Drug Application (NDA) to the FDA for the approval of sofosbuvir, a once-daily, oral nucleotide analogue for the treatment of chronic hepatitis C virus (HCV) infection.

The NDA supports the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with HCV genotype 2 and 3 infection, and for sofosbuvir in combination with RBV and pegylated interferon for the treatment of treatment-naive patients with HCV genotypes 1, 4, 5 and 6 infection.

“Current therapies are not suitable for large numbers of patients with HCV infection and are challenging to take and tolerate,” said John C. Martin, PhD, chairman and CEO of Gilead Sciences. “Sofosbuvir’s antiviral potency, safety profile and once-daily administration have the potential to improve cure rates by simplifying and shortening therapy for patients with this disease.”

The sofosbuvir NDA is supported primarily by four Phase III studies (NEUTRINO, FISSION, POSITRON and FUSION) in which 12 or 16 weeks of sofosbuvir therapy was found to be superior or noninferior to currently available treatment options or historical controls. This positive result was based on the proportion of patients who exhibited a sustained virologic response (SVR) 12 weeks after completing therapy. Patients who achieve SVR at 12 weeks are considered “cured” of HCV infection, according to a press release from Gilead.

Sofosbuvir is a nucleotide analogue inhibitor of the HCV NS5B polymerase protein, which plays an essential role in HCV replication. Unlike RBV and pegylated interferon, sofosbuvir is a direct-acting agent.

Sofosbuvir is an investigational product, and its safety and efficacy have not yet been established.

—Based on a press release from Gilead Sciences

—Based on a press release from Roche

Janssen Submits New Drug Application for HCV Protease Inhibitor, Simeprevir Janssen Research & Development, LLC, recently announced that it has submitted a New Drug Application to the FDA seeking approval for simeprevir (TMC435), for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in adult patients with compensated liver disease.

Simeprevir is an investigational NS3/4A protease inhibitor administered as a 150-mg capsule once daily with pegylated interferon and ribavirin. It is believed to work by blocking the HCV protease enzyme that enables the virus to survive and replicate in host cells.

“Hepatitis C is a complicated disease and genotype 1 hepatitis C can be particularly difficult to cure,” said Wim Parys, global head of development, infectious diseases and vaccines at Janssen. “Given the complexity and diversity of the patient population, physicians need multiple options to provide their patients a chance at treatment success. The U.S. filing represents an important step forward in bringing simeprevir to market and in helping to battle this challenging disease.”

The regulatory submission for simeprevir is

supported in part by data from three Phase III studies: QUEST-1 and QUEST-2 in treatmentnaive patients, and PROMISE in patients who have relapsed after previous interferon-based treatment for HCV. In each study, participants were treated with one 150 mg simeprevir capsule once daily for 12 weeks, plus pegylated interferon and ribavirin for 24 or 48 weeks. Primary efficacy data from these studies will be presented in the near future, the company said.

—Based on a press release from Janssen Research & Development, LLC

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2013

CAREER OPPORTUNITIES

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F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

FDA Approves Zortress To Prevent Organ Rejection In Patients Undergoing Liver Transplantation The FDA has approved Zortress (Novartis), a mammalian target of rapamycin (mTOR) inhibitor, for the prophylaxis of organ rejection in adult patients following liver transplantation. Zortress is already approved for use in adults who have received a kidney transplant in the United States.

Calcineurin inhibitors, such as tacrolimus, are part of the standard-of-care treatment regimen for immunosuppression in liver transplantation, but they can contribute to adverse reactions, including impaired renal function. Zortress works by binding to a protein called mTOR, and acts synergistically with calcineurin inhibitors, offering an opportunity to lower exposure to calcineurin inhibitors.

“While prevention of acute organ rejection is a key priority for physicians following liver transplantation, managing other health risks, including impaired renal function associated with calcineurin inhibitor treatment, is also critical,” John Fung, MD, PhD, director, Transplantation Center, Cleveland Clinic Foundation, in Ohio, said in a statement issued by Novartis.

A large independent registry of nearly 70,000 patients who received a non-renal, solid organ transplant between 1990 and 2000 showed that the incidence of chronic renal failure was greater in liver transplant recipients than in recipients of

all other solid organ transplants, except intestinal transplants (Ojo A et al. N Engl J Med 2003;349:931-940).

“With the approval of Zortress, the first mTOR inhibitor approved for liver transplant patients, we have a new treatment option that has the potential to address the unmet medical need for maintaining renal function without compromising acute rejection rates—and that’s important for patients and physicians.”

The FDA approval was based on results from a 12-month, Phase III, multicenter, open-label, randomized controlled study conducted in 719 liver transplant patients, starting 30 days posttreatment. Patients were randomized to one of three groups: Zortress (C0 3-8 ng/mL) plus reduced-exposure tacrolimus (C0 3-5 ng/mL; n=245); Zortress (C0 6-10 ng/mL) followed by tacrolimus withdrawal at four months (n=231); or standard exposure tacrolimus only (C0 6-10 ng/mL; n=243). All three study arms were treated twice daily and all included corticosteroids for at least six months post-transplant. Enrollment into the tacrolimus withdrawal arm was prematurely halted due to a higher incidence of acute rejection episodes and adverse reactions leading to treatment discontinuation clustered around the

Photo courtesy of Novartis

time of tacrolimus elimination at four months post-randomization. Therefore, a treatment regimen of Zortress with tacrolimus elimination is not recommended.

Study results showed that Zortress plus reduced-exposure tacrolimus was comparable to standard-exposure tacrolimus with respect to efficacy failure. The incidence of efficacy failure was lower in the Zortress plus reduced-exposure tacrolimus group compared with the tacrolimus control group at month 12 (9% vs. 13.6%, respectively).

Only physicians experienced in immunosuppressive therapy and management of transplant patients should use Zortress. Potential adverse effects include lymphomas and other malignancies, serious infections, kidney graft thrombosis and calcineurin inhibitor–induced nephrotoxicity.

—Based on a press release from Novartis

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2013

63

FibroScan® Cleared By FDA for Sale in the United States Echosens™ and Sandhill Scientific, Inc., are pleased to announce that the FibroScan® 502 Touch device, including the M+ and XL probes, received 510(k) clearance from the FDA on April 5. The companies are now ready to market this pioneering technology in the United States.

FibroScan® 502 Touch, the first device using quantitative elastography for the clinical management of patients with liver disease, is indicated for the noninvasive measurement of shear wave speed at 50 Hz in the liver, which is used as an aid in the clinical management of patients with liver disease.

monitored using ultrasound. Studies demonstrated that shear wave speed (and liver stiffness) measured by FibroScan® strongly correlates with liver fibrosis.

FibroScan® has been validated with more than 660 peer-reviewed publications. Moreover, the use of FibroScan® also is mentioned in guidelines and recommendations in different regions of the world,

including the World Health Organization, the European Association for the Study of the Liver and the Asian Pacific Association for the Study of the Liver.

FibroScan® will be available exclusively in the United States through Sandhill Scientific, Inc. Now in its 32nd year, Sandhill Scientific continues to be a leader in gastrointestinal diagnostic

BRIEF SUMMARY Please consult package insert for full prescribing information.

INDICATIONS AND USAGE APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older.

DOSAGE AND ADMINISTRATION The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO capsules) orally once daily in the morning. APRISO may be taken without regard to meals. APRISO should not be co-administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO. CONTRAINDICATIONS APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules.

WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine.

It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease.

In animal studies, the kidney was the principal organ for toxicity.

Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. Hypersensitivity Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO capsules or to other compounds that contain or are converted to mesalamine.

Photo courtesy of Sandhill Scientific, Inc.

Based on patented technology called Vibration-Controlled Transient Elastography, FibroScan® is used to assess shear wave speed in the liver (expressed in meters per second) and equivalent stiffness (expressed in kilopascals) in a simple, fast, non-invasive and virtually painless way. A mechanical actuator located in the probe induces a 50 Hz shear wave that propagates through the liver and is

Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease.

ADVERSE REACTIONS APRISO was studied in two placebo-controlled trials (n=367 treated with APRISO) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study.

In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%).

The most common treatment-related adverse events occurring in at least 3% of adult patients taking 1.5 g/day of APRISO and at a rate greater than placebo were headache (11% vs 8% for placebo), diarrhea (8% vs 7% for placebo), upper abdominal pain (5% vs 3% for placebo), nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo), and sinusitis (3% vs 3% for placebo).

innovation. From the ZepHr® Impedance/pH Reflux Monitoring System to the new inSIGHT Ultima Manometry Platform, Sandhill provides a broad spectrum of diagnostic solutions enhancing patient care.

Echosens™ is a subsidiary of Inner Mongolia Free Han & Mongolia Pharmaceutical Co. Ltd. (China).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/ kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Mesalamine is known to cross the placental barrier.

Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised when APRISO is administered to a nursing woman.

Pediatric Use Safety and effectiveness of APRISO capsules in pediatric patients have not been established.

Geriatric Use Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing APRISO. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine therapy.

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. (see WARNING AND PRECAUTIONS) Phenylketonuria Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 0.56 mg of phenylalanine.

CLINICAL STUDIES Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis.

Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index1 (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s rating of disease activity.

Patients were randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six months.

In both studies, the proportion of patients who remained relapse-free at six months was greater for APRISO than for placebo. In study 1 (N=305), 68% of subjects taking APRISO were relapse-free at 6 months EOT vs 51% with placebo (P<0.001). In study 2 (N=257), 71% of subjects in the APRISO group were relapse-free at 6 months EOT vs 59% for placebo (P=0.046).

HOW SUPPLIED APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the capsule.

NDC 65649-103-02 NDC 65649-103-01

Bottles of 120 capsules Bottles of 4 capsules

STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature.

Reference: 1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987;92:1894-1898.

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

GM 08/22-1

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Maintain UC remission with a low average co-pay

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APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials.

The most common adverse reactions (incidence ≥3% and >placebo) with APRISO in clinical trials were headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, influenza and influenza-like illness, and sinusitis1 *Average co-pay (all payers), Wolters Kluwer Health, August 2012. †Fingertip Formulary®, November 2012. ‡VA Healthcare System, October 2012.

Please see Brief Summary of complete Prescribing Information.

Please see complete Prescribing Information available at AprisoRx.com.

APRISO® and INTELLICOR® are registered trademarks of Salix Pharmaceuticals, Inc. ©2013 Salix Pharmaceuticals, Inc. All rights reserved. GM 12/95

See reverse side of APRISO Card for eligibility criteria. For help processing this card, call 1-855-740-3034.

Transition to APRISO, an affordable, once-daily ulcerative colitis (UC) therapy for your adult patients Average co-pay of less than $35 (all tiers)* Extensive formulary coverage with ~90% covered lives† #1-prescribed 5-ASA in the VA Health Care System‡

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Ulcerative Colitis: Diagnosis and Treatment

T

he greatest

ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

BRIAN BOSWORTH, MD Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

ARUN SWAMINATH, MD

challenge for clinicians who

treat patients with inflammatory bowel disease (IBD) is to move from symptomoriented (step-up) strategies toward prevention-oriented (early intervention) strategies aimed at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized approach to the treatment of patients with ulcerative colitis (UC).

Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

Challenging the Traditional IBD Diagnosis

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb a

NewYork-Presbyterian Hospital/ Weill Cornell Medical Center New York, New York b Weill Cornell Medical College New York, New York c Columbia University College of Physicians and Surgeons New York, New York

Traditionally, IBD has been divided into 2 distinct entities: UC and Crohnâ&#x20AC;&#x2122;s disease (CD). A nuanced view presents IBD as an immuno-inflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease.

One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

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classify CD. Three distinct manifestations of CD have been described—inflammatory, fistulizing, and fibrostenotic.1-3 However, Crohn’s colitis has not been well defined in the literature.4 Some patients present with CD-like features—such as UC with rectal sparing or UC with nonepithelial granulomas. Other manifestations of the heterogeneity of colitis are a superficial mucosal CD involving left-sided refractory colitis with rectal involvement (which may actually represent a type of mixed collagenous colitis or vascular collagen disorder still undefined), rectal disease with cecal patch, and a form of UC with post-treatment alterations.4 The many forms of UC (eg, ulcerative proctitis, leftsided colitis, universal colitis) led Brooke5 to suggest that, rather than a single disease entity, UC represents a pathologic state with many etiologies. Indeterminate colitis (IC) might represent part of an immunologic continuum, rather than a well-defined clinical subset of UC and CD.6,7 IBD is a dysregulated immune response to luminal microbial antigens. Serologic markers may provide a window for observing an abnormal antibody–antigen response and may help identify patients at risk for rapid progression of disease who may benefit from early intervention.8 Molecular diagnostics, such as antibody serology, biomarkers, and genotyping hold the promise of enhancing the understanding of IC and stratifying patients with IBD on the basis of immunophenotypes and immunogenotypes.9 Differential diagnosis is increasingly recognized as important in distinguishing active inflammation from medication–pseudo-refractory IBD—which may include infections (eg, Clostridium difficile, cytomegalovirus), overlap with irritable bowel syndrome, celiac disease, lactose and/or fructose intolerance, dietary indiscretion, bile acid diarrhea, and obstructive stricturing or fistulizing CD requiring surgery—and in stratifying optimal therapeutic response to biologics and immunosuppressives.10 In selected patients with moderate to severe active IBD, early intervention with effective therapy is associated with significant improvement in mucosal healing and reduction in the progression of disease.11-13

Molecular Classification of IBD IBD nomenclature does not accurately reflect the complexity of clinical phenotype. Although the role of serum antibody markers remains controversial, using a combination of markers enhances accuracy and specificity in classifying IBD-related aberrant immunophenotypes. The emerging role of molecular diagnostics is vital in characterizing the immunologic heterogeneity of

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IBD, and will be a bridge linking clinical immunophenotypes with genotypes.14,15 More than 140 genes associated with IBD have been identified using genome-wide association studies (GWAS), but account for only 25% of the heritability.16 At present, common gene variants identified by GWAS will be too insensitive and nonspecific to predict disease in unaffected patients. New genes continue to highlight host microbial interactions,17-20 and serologic markers indicate dysregulated antibody–antigen immune responses.

Differentiation between types of IBD becomes important in stratifying therapeutic strategies. Poor therapeutic response is an indication for surgery in nearly one-third of patients with UC and approximately 50% to 70% of patients with CD. Patients with refractory left-sided colitis or IC may benefit from serologic testing, in addition to documentation of clubbing and oral aphthae.15 Serologic signatures have proven helpful in patient stratification. The incorporation of validated biomarkers, such as fecal calprotectin, which has been shown to correlate with endoscopic disease severity in both CD and UC,21 into clinical decision making also may help identify patients with active disease.

Serologic diagnostic and biomarker testing provides a molecular snapshot of patients with IBD. New markers and prospective trials are required to correlate immunologic, molecular, and clinical patterns of IBD, and will advance the risk assessment of patients, the selection of prevention-oriented therapies, and the science of IBD.

Epidemiology and IBD Subtypes Epidemiologic data on IBD are fractionated into the pigeonholes of separate diagnoses, with an incidence of 7 to 9 per 100,000 and a prevalence of 200 to 250 per 100,000 for UC; the incidence and prevalence of CD are 6 to 8 per 100,000 and 130 to 200 per 100,000, respectively.22-24 Although there are patients who fall more clearly into one category than another, the concept of IC is poorly defined and therapeutic guidelines are lacking.

The majority of patients with IBD have moderate disease. Three-fourths of patients have active UC,25 and two-thirds of patients with CD have moderate to severe disease that requires alternatives to treatment with mesalamine therapies.26

Treatment Options for UC The treatment goals for patients with IBD are universal: induce remission as quickly as possible, maintain remission as long as possible, facilitate mucosal healing, improve quality of life, minimize toxicity, and minimize cost.

For patients with UC, oral and rectal 5-aminosalicylic acid (5-ASA) agents (including free 5-ASA and 5-ASA prodrugs), corticosteroids (IV [eg, hydrocortisone] or oral [eg, prednisone, methylprednisolone]), immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP]), and cyclosporine are used to induce remission.

Uceris, a new once-daily, extended-release formulation of budesonide–MMX Multi Matrix System (MMX) is effective for inducing remission in adults with mild to moderate UC and is associated with significantly fewer systemic adverse events (AEs) than conventional corticosteroids.

The role of Uceris in maintaining remission in ulcerative colitis needs to be further evaluated with prospective studies. Comparison of mesalamine and budesonide for both induction and maintenance of UC remains to be established.27-29 For maintenance of remission of UC, 5-ASAs and 6-MP or AZA may be used. Additionally, the anti-tumor necrosis factor (TNF) agents infliximab, and more recently adalimumab, are approved for the reduction of signs and symptoms, induction of clinical remission and mucosal healing, and elimination of corticosteroid use in patients with moderately to severely active UC who have had an inadequate response to conventional therapies.30 Probiotics and novel antibiotics (eg, rifaximin) have the potential to revolutionize the treatment of patients with IBD.31,32 For example, anti-inflammatory interleukin (IL)-10 levels have been associated with Bifidobacterium infantis.33 A greater understanding of gut microecology and the gut microbiome is emerging and further clinical trials are warranted.34 Colitis-associated arthritis35 responds best to sulfasalazine and this may be related to the antibiotic properties of sulfapyridine rather than the anti-inflammatory properties of 5-ASA.36,37

5-ASA: First-Line Therapy MECHANISMS

OF

ACTION

The specific goals of 5-ASA therapy are to quickly induce complete remission, facilitate mucosal healing, and minimize steroid use and toxicity. The effectiveness of the compound is related to its mucosal concentration,38 and systemic dosages remain low after oral sulfasalazine and rectal 5-ASA administration.39 The putative anti-inflammatory actions of 5-ASA include modulation of inflammatory cytokine production, decreased transcriptional activity of nuclear factor-kappa B (NF-κB) by modulating RelA/p65 phosphorylation, and inhibition of the biosynthesis of prostaglandins and leukotrienes.40 One proposed mechanism of action of 5-ASA is the

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Figure 1. Disease distribution of ulcerative colitis at presentation to the physician’s office.

Based on reference 44.

inhibition of the cyclooxygenase (COX) and 5-lipoxygenase pathways of arachidonic acid metabolism, resulting in a decrease of proinflammatory prostaglandins and leukotrienes.41 The role of the COX pathway and prostaglandin biosynthesis in IBD remains to be elucidated. Attention has shifted from the arachidonic acid cascade to NF-κB. The discovery of the role of nucleotide-binding oligomerization domain 2 in the activation of NF-κB emphasizes the importance of NF-κB in the inflammatory signaling cascade and its interaction with luminal bacterial antigens and genetic susceptibility. In vitro studies demonstrate that sulfasalazine inhibits NF-κB, which provides evidence in support of the direct biologic efficacy of 5-ASA. Recently, it has been postulated that 5-ASA leads to peroxisome proliferator–activated receptor-gamma (PPAR-γ) transcription and protein expression.42 The PPARs are members of the nuclear receptor superfamily. They are activated by fatty acids and are involved in the complex interplay of metabolic and nutritional signals leading to transcriptional responses. They are expressed in high levels in the colonic epithelium and their ligands are involved in regulation of inflammation.

A randomized placebo-controlled trial of rosiglitazone

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Table. Mechanisms of Release of 5-ASA–Containing Drugs Type of 5-ASA

Mechanism of Action

Advantage

Indication

Time-released, moisturedependent ethylcelluloseencapsulated mesalamine travels in solution and allows free 5-ASA mesalamine to diffuse out of the ethylcellulose beads and begin releasing in the upper intestines and continue throughout the small and large intestines.

Independent of pH or bacteria; mucosal delivery of mesalamine is less affected by rapid intestinal transit time (ie, diarrhea).95

Free 5-ASA (mesalamine) is indicated in patients with proximal disease activity, severe diarrhea, strictures (1-mm ethylcellulose microspheres offer advantages), pouchitis (the constant, moisture-dependent release may provide advantages), and postoperative anastomosis.

The pH-dependent mesalamine preparations are coated with an acrylate resin and are released at variable pH levels, between 6.0 and 7.0 in the distal ileum and colon.

(The pH in the ileum and ascending colon is 7.0.)

Free 5-ASA (mesalamine) A pH-dependent delivery dosage can be maximized system is indicated in ileoto 4.8-6 g daily, equivalent colonic disease. to a triple dose of sulfasalazine (12 g) with significantly less toxicity. Lialda is a 1.2-g tablet that is a high-dose, delayed-release, pH-dependent mesalamine formulation.68,70,71 Oncedaily dosage is between 2.4 and 4.8 g (2-4 tablets).

Apriso once-daily 1.5-g granulated delayed- and extended-release mesalamine (four 0.375-g capsules) travels in solution.47-49

Diffusion-Dependent Mesalamine, controlledrelease (Pentasa, Shire)

pH-Dependent Mesalamine, delayedrelease, pH 7.0 (Asacol, Warner Chilcott) MMX mesalamine, pH 7.0 (Lialda, Shire) Mesalamine, delayedrelease, pH>6.0 (Eudragit-L, Evonik) Mesalamine delayedand extended-release, pH 6.0 (polymer core of slow-release mesalamine; Apriso, Salix)

Mesalamine, delayedrelease, pH 7.0 (Delzicol, Warner Chilcott

(a PPAR-γ ligand) demonstrated efficacy in treating mild to moderate UC.43 However, despite these numerous experimental studies, the mechanism of action of 5-ASA remains elusive.

Clinicians should question whether the site of 5-ASA release is a determinant in optimizing and individualizing therapy. Two therapeutic strategies expose jousting views: One is that all 5-ASA preparations are equivalent and that dose escalation leads to optimization; the other is that differences in the mode of 5-ASA delivery translate into differences in clinical efficacy. Often overlooked is the distribution of UC— more than 50% of patients have left-sided disease

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(Figure 1)44—as well as the variability in colonic pH. Colonic pH may be lower in patients with UC than in those without IBD; thus, employing 5-ASA formulations that release at a lower pH (eg, granulated mesalamine [Apriso, Salix Pharmaceuticals]) may improve drug delivery to the colon while avoiding release in the small intestine.45 Both mesalamine (free, unconjugated 5-ASA) and mesalamine prodrugs (azo-bonded 5-ASA) have similar modes of action. Sulfasalazine, the archetypal azobonded 5-ASA designer drug, is engineered to release free 5-ASA in the colon, protecting it from proximal absorption.36,37 Intolerance and hypersensitivity to

Table. Mechanisms of Release of 5-ASA–Containing Drugs (continued) Type of 5-ASA

Mechanism of Action

Advantage

Indication

In these azo-bonded 5-ASA forms, the molecule reaches the colon primarily intact and the azo bond is cleaved by colonic bacterial azo-reductase, thereby releasing free, unconjugated 5-ASA (mesalamine). A highdose, 1.1-g balsalazide tablet allows for lower pill burden and twice-daily dosing.52,53

This formulation is indicated for patients with universal and distal colitis.

Advantages of topical preparations include direct exposure to diseased mucosa.

These agents are indicated for patients with left-sided colitis and proctitis.

Colonic flora–dependent, azo-bonded Sulfasalazine (Azulfidine, Pfizer) Sulfasalazine, delayedrelease (Azulfidine EN-Tabs, Pfizer) Balsalazide disodium (Colazal, Salix) Balsalazide disodium (Giazo, Salix) Olsalazine sodium (Dipentum, Pfizer)

There are currently 3 variations of colonic-releasing, azo-bonded 5-ASA drugs: 1. Sulfasalazine consists of 5-ASA bonded to sulfapyridine; 2. Balsalazide links an inert polymer of 4-aminobenzoyl-B-alanine to 5-ASA; 3. Olsalazine consists of 2 molecules of 5-ASA linked to each other.

Topical/rectal formulations Mesalamine suppository Rectal preparations include (Canasa, Aptalis) 5-ASA suspensions (4-g mesalamine enema and Mesalamine enema 500-mg mesalamine sup(Rowasa, Meda pository) that are instilled Pharmaceuticals) directly into the rectum.

5-ASA, 5-aminosalicylic acid; MMX, Multi Matrix System

the sulfapyridine moiety limit the dose of sulfasalazine and have led to the development of new 5-ASA– containing analogs. The newer topical and oral 5-ASA agents are delivered to different anatomic sites, ideally corresponding to the distribution of active disease (Table). Although these agents are less toxic than sulfapyridine, mesalamine allergies (eg, high fevers, allergic pneumonitis) and intolerance (eg, worsening IBD symptoms) may occur and discontinuation of 5-ASA therapy my be required. Interstitial nephritis has been reported with the 5-ASA moiety alone46 and mandates periodic renal function monitoring.

TREATMENT

OF

UC

Until the introduction of balsalazide, all of the newer 5-ASA agents had been shown to induce and maintain remission of UC nearly as well as sulfasalazine and usually as well as one another. The advantage of some of the newer 5-ASA preparations is that patients can tolerate higher doses. Recently, novel dual-delivery systems

(delayed- and extended-release) allow for effective dose de-escalation, with lower doses of active 5-ASA delivered to the site of active colitis.47-49 In the first head-to-head trial comparing an equimolar dose of balsalazide (6.75 g) with pH-dependent mesalamine (2.4 g), balsalazide showed superior efficacy in patients with new-onset left-sided UC (62% vs 37%) and shorter time to response (10 vs 25 days); response rates also were higher in patients with right-sided UC, although the difference was less significant compared with patients with left-sided disease.50 A stratification study confirmed that among patients with new-onset left-sided UC, more than 60% of those treated with balsalazide were in remission at 1 month compared with 40% of those treated with pH-dependent mesalamine.51 Additionally, patients with right-sided UC who were treated with balsalazide had less rectal bleeding, better sigmoidoscopic-evident healing, and improved stool frequency. A twice-daily balsalazide dosing regimen (three 1.1-g tablets, twice daily, for a total of 6.6 g/d) has been

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shown to be well tolerated and effective in relieving signs and symptoms of mild to moderate UC.52,53 This regimen reduces pill burden and should improve adherence and convenience for patients.

Levine et al54 conducted a randomized, double-blind study comparing 2 doses of balsalazide (6.75 and 2.25 g) and mesalamine (2.4 g) in patients with active, mild to moderate UC. At week 8, rates of remission were similar for all 3 treatment groups, as were safety profiles. The primary difference between balsalazide (6.75 g) and mesalamine appeared to be the time to symptom resolution (10 vs 25 days, respectively). Kornbluth et al55 compared the colonic mucosal concentration of 5-ASA in patients treated with a mean of 6.75 g per day of balsalazide with those treated with a mean of 3.74 g per day of pH 7.0– dependent mesalamine and demonstrated that patients who received balsalazide had significantly higher mean mucosal concentrations of 5-ASA than patients who received mesalamine.

Because of the predominance of left-sided disease, the combination of oral and topical aminosalicylates is critical in inducing and maintaining remission.56,57 Safdi et al56 elegantly demonstrated that although topical mesalamine was more effective than oral in patients with left-sided UC, the combination of 2.4 g of oral mesalamine and mesalamine enemas produced earlier and more complete cessation of rectal bleeding.

For maintenance of remission, D’Albasio et al57 found that a combination of 1.6 g of oral mesalamine with twice-weekly mesalamine enemas produced higher rates of remission compared with oral therapy alone (61% vs 31%, respectively). Topical mesalamine (enema and suppository formulations), used as infrequently as twice per week, is effective in maintaining remission in patients with distal colitis. A systematic review compared the efficacy of combined oral and topical 5-ASA with oral therapy alone and found a significant increase in remission rates in mild to moderate UC with combined therapy, and intermittent topical therapy was superior to oral therapy in maintaining remission in quiescent UC.58 Biddle et al59 established that 75% of patients (9 of 12) randomized to receive mesalamine enemas remained in remission at 1 year compared with 85% of patients (11 of 13) on placebo who had relapsed by week 16. Similarly, mesalamine suppositories were associated with long-term remission in patients with ulcerative proctitis; at 12 and 24 months, 86% and 89% of patients on placebo had relapsed compared with 32% and 46% of patients treated with mesalamine suppositories, respectively.60 A meta-analysis established that in patients with left-sided UC and ulcerative proctitis,

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topical mesalamine showed greater efficacy and fewer side effects than oral therapies and topical steroids.61 Additionally, Campieri et al62 demonstrated that mesalamine suppositories were effective in inducing remission in patients with ulcerative proctitis (distal colitis up to 20 cm). In that study, 74% of patients who received mesalamine suppositories (1.5 g) achieved clinical remission at week 4 compared with 39% of patients who received placebo.

The pH-sensitive 5-ASAs were evaluated in a placebocontrolled trial in patients with active mild to moderate UC.63 In contrast to a 71% maintenance of remission rate, complete remission was induced in 24% of patients on mesalamine 4.8 g, 9% of patients on mesalamine 1.6 g, and 5% of patients on placebo.64 Partial response was achieved in 50% of patients in the high-dose mesalamine group compared with 18% in the low-dose group and 13% in the placebo group.63 The ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) II trial found 4.8 g of delayed-release mesalamine (Asacol) to be superior to 2.4 g in patients with moderate UC, with response rates of 72% and 59%, respectively; remission rates were similar in both groups at 24%.65 ASCEND I and II were the first head-to-head— although non–placebo-controlled—comparisons of 2.4 versus 4.8 g of Asacol in patients with mild to moderate UC. In ASCEND III, the response rate at 6 weeks was 70% for patients taking 4.8 g of Asacol (6 tablets, 800 mg each) compared with 66% for those taking 2.4 g of Asacol (6 tablets, 400 mg each).66 Delzicol, released in early 2013, is a new delayedrelease capsule formulation of mesalamine that has been shown to be equivalent to Asacol delayed-release tablets.67 It is available as a 400-mg delayed-release capsule. The prescribing information indicates that patients should take 800 mg, three times daily, for a total of 2.4 g daily for the treatment of mildly to moderately active UC. For maintenance of remission, patients should take 1.6 g daily, in divided doses. The medication should be taken at least 1 hour before or 2 hours after a meal.

The dosing for Delzicol could be problematic in clinical practice. For example, patients may find it difficult to take the drug three times a day when it is supposed to be ingested 1 hour before or 2 hours after a meal.

Because medication compliance is an extremely important issue in treating patients with UC, this may present a significant challenge to long-term compliance.

A high-strength pH–dependent formulation of 5-ASA—MMX mesalamine (Lialda, Shire), taken once or twice daily, has been well tolerated and has induced remission in patients with mild to moderate UC. The formulation is a 1.2-g tablet and has been evaluated

for twice-daily (one 1.2-g tablet, twice daily; 2.4 g/d) and once-daily (four 1.2-g tablets, once daily; 4.8 g/d) administration.68-71 Lichtenstein et al68 showed that after 8 weeks of treatment, rates of clinical and endoscopic remission were significantly higher for patients taking MMX mesalamine compared with patients taking placebo (34.1% and 29.2% for 2.4 g/d and 4.8 g/d, respectively, vs 12.9% for placebo; P<0.01). Increasing the dose to 4.8 g per day for an additional 8 weeks resulted in clinical and endoscopic remission and symptom resolution for nearly 60% of patients in a median time of 15 days.70 In a separate study by Kamm et al, once- or twice-daily MMX mesalamine resulted in maintenance of clinical and endoscopic remission.71 A granulated pH 6.0 delayed and extended release formulation of 5-ASA (Apriso) with a polymer matrix core has been approved by the FDA for the maintenance of remission at 1.5 g per day. Lichtenstein et al72 demonstrated maintenance of remission in nearly 79% of patients who switched from different 5-ASA formulations compared with almost 60% who maintained remission on placebo. In a European dose-ranging study that evaluated this pH 6.0–releasing granulated formulation of 5-ASA in patients with mildly to moderately active UC, remission rates were 66% for patients taking 3 g per day (1 g, three times daily), 50% for those taking 1.5 g per day (0.5 g, three times daily), and 55% in those taking 4.5 g per day (1.5 g, three times daily).47 Although there was no placebo arm in the study, clinical remission rates in all 3 treatment groups were high.

With the exception of endoscopic improvement, which was better in the 3-g per day group than in the 1.5-g per day group, no significant differences among the 3 groups were observed. These findings suggest that the novel delivery mechanism of granulated mesalamine may lead to release of active drug at the site of active disease allowing for effective dose de-escalation.

In another study, 2 doses of mesalamine granules—a 3-g dose given once daily and a 1-g dose given 3 times per day—were similarly safe and effective in producing clinical and endoscopic remission in patients with mildly to moderately active UC.48 This provides evidence that decreasing the dosing frequency may improve adherence to medication while maintaining efficacy.

Once-daily, 1.5-g granulated mesalamine delayedrelease (Eudragit-L, Evonik; dissolving at pH>6.0) and extended-release (polymer matrix core, containing slowly eluting mesalamine) have been shown to maintain remission in nearly 80% of patients who switched from different 5-ASA formulations compared with almost 60% who maintained remission on placebo.49 Dose de-escalation with granulated mesalamine 1.5 g

per day may improve long-term adherence to medication and remission. Mesalamine granules also have demonstrated higher rates of induction of remission of UC compared with budesonide (54.9% vs 39.5%).73 And in a comparison of MMX mesalamine and Asacol (Warner Chilcott), patients with UC who took MMX mesalamine maintained remission longer than those on Asacol.74 A recent meta-analysis confirmed the benefit of 5-ASA for inducing and maintaining remission in UC.75 The optimal dose appeared to be 2.4 g per day, with no apparent benefit from increasing the dose. Similarly, the optimum dose to prevent relapse was 2.0 to 2.4 g per day. These recommended doses are expressed in mesalamine or equivalent.

Initial mesalamine dosing strategies followed the divided dosing paradigm used with sulfasalazine, which was developed to minimize sulfapyridinerelated AEs. Several studies have assessed the safety and efficacy of once-daily mesalamine administration.

The PODIUM (Pentasa Once Daily In Ulcerative colitis for Maintenance of remission) trial assessed the use of pH-sensitive mesalamine (Pentasa, Shire) 2 g per day taken as a single daily dose versus 2 divided doses over 1 year in left-sided UC.76 For once-daily dosing and divided dosing, remission rates were 69% versus 61%, respectively, and mucosal healing rates were 84% versus 78.6%, respectively, and there was no difference in AEs. The QDIEM (QD Dosing Investigation for Efficacy in UC Maintenance) study, a large, randomized controlled trial conducted by Sandborn et al,77 assessed Asacol 1.6 and 2.4 g per day in once- or twice-daily divided doses for maintenance of remission in 1,023 patients with mild to moderate UC in clinical remission.

More than 90% of patients in both dosage groups at 6 months, and 85.4% at 12 months, remained in remission without differences in AEs or treatment withdrawal rates. An active-control randomized trial of 824 patients with UC in clinical remission by D’Haens et al78 demonstrated noninferiority of MMX mesalamine 2.4 g once daily compared with pH-sensitive mesalamine 0.8 g twice daily. The aforementioned studies were not placebo-controlled but did demonstrate similar efficacy and safety profiles for the assessed end points. Furthermore, a meta-analysis of 10 randomized controlled trials in UC demonstrated no difference in the rates of maintenance of remission in patients with quiescent UC treated with once-daily mesalamine and also showed a mild but significant benefit in induction of remission in patients with mildly active UC, with improved adherence and a similar AE profile.79 A recent cost–benefit analysis suggested that inflammation-targeted treatment using 5-ASA therapy for

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patients with stool samples positive for inflammation may cost less than continuous treatment for all UC patients.80 Further studies correlating tight inflammation control and inflammatory biomarker monitoring are warranted.

MESALAMINE THERAPY DURING PREGNANCY In pregnant patients, 5-ASA and its metabolite, acetyl-5-ASA clearly cross the placenta and thus are found in both maternal and fetal plasma in women on mesalamine therapy.81 Currently, per FDA recommendations, all mesalamine therapies, except for olsalazine and Asacol/ Asacol HD, are considered pregnancy safety classification B. In 2010, Asacol and Asacol HD were switched to a classification of C for safety in pregnancy by the FDA. Prior studies of mesalamine performed during organogenesis in rats and rabbits at oral doses up to 480 mg/ kg per day showed no evidence of fetal malformations.

These doses represented approximately 1.6 and 3.2 times the recommended human dose (based on body surface area). The class transition was based on more recent animal studies showing that the inert ingredient of Asacolâ&#x20AC;&#x2122;s enteric coating, dibutyl phthalate (DBP), is associated with adverse reproductive aberrations when given in very high doses.82 The maximum daily human intake of DBP is about 48 g. Published reports in rats exposed to DBP in utero at doses 17 times the human dose showed reproductive anomalies in male offspring, specifically an injury to androgenic-dependent development. Even higher doses of DBP, approximately 84 times the human dose, resulted in worse outcomes for these male rat offspring, including cryptorchidism, hypospadias, atrophy or agenesis of sex accessory organs, reduced daily sperm production, and permanent retention of nipples.

The female offspring appeared to remain unaffected by these same doses. Exposure to DBP at doses equivalent to 106 times the human dose resulted in increased incidences of cleft palate and skeletal abnormalities in both female and male offspring.

It is important to note that the dosage of Asacol/Asacol HD appears to be the critical component in causing these adverse pregnancy outcomes in rats. Before this pregnancy reclassification of Asacol, gastroenterologists had been using this particular mesalamine preparation in varying doses (the maximum dose being 4.8 g daily) for the past decade in pregnant women with IBD without any AEs observed in the mothers or offspring. It appears that Asacol and Asacol HD can be used during pregnancy when administered in the appropriate doses as suggested by studies in human patients and the vast clinical experience of many IBD specialists.

The PIANO registry is a prospective cohort of pregnant women with IBD that has enrolled more than 1,000

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patients to date.83 The analysis of the effect of mesalamine on pregnancy outcomes is pending. Early results have confirmed data from earlier studies that suggest no increase in congenital malformations in children born to mothers exposed to immunosuppressants or anti-TNF drugs compared with mothers who were not exposed to either group of medications. Notably, there was an increase in the number of infections in infants born to mothers exposed to the combination of thiopurines and anti-TNF agents during pregnancy, which merits closer investigation. Developmental milestones were similar among all exposure groups and will be followed in children up to age 4 years.

OPTIMIZING ORAL 5-ASAS Although there are no prospective studies evaluating combinations of oral 5-ASA drugs, combination therapy may be considered in patients who fail to respond to mesalamine monotherapy or 5-ASA prodrug monotherapy. 5-ASA nonresponders may benefit from a combination of pH-dependent polymer-coated mesalamine, moisture-dependent mesalamine, and azo-bonded 5-ASA preparations (eg, sulfasalazine, olsalazine, balsalazide). A flexible dosing schedule in which the patient actively modifies the combination therapy based on clinical response may shorten the duration to response. Lastly, a flexible dosing schedule that combines oral and topical 5-ASA agents is an effective therapeutic strategy that should not be overlooked. With the variety of 5-ASA preparations available, optimization of 5-ASA therapy may be viewed as a dynamic rather than a static process. In a patient not responding to an initial 5-ASA therapeutic choice, dosage may be optimized (ie, escalated, de-escalated), and oral preparations may be combined with each other, as well as with topical agents, in an attempt to optimize delivery of 5-ASA to the site of active disease.

Anti-TNF Therapeutic Options There is increasing evidence that infliximab is useful for induction of remission in patients with UC who are steroid-refractory or steroid-dependent despite adequate doses of thiopurine, or who are intolerant of these medications. In ACT (Active Ulcerative Colitis Trials) 1 and 2, researchers evaluated the efficacy of infliximab in patients with severe UC.84 Patients with moderate to severe disease were randomized to receive IV infliximab (5 or 10 mg/kg) at weeks 0, 2, and 6, and every 8 weeks thereafter, or placebo.

In these trials, 64% to 69% of patients who received infliximab 5 mg/kg exhibited a clinical response at week 8 compared with 29% to 37% of patients who

received placebo. Infliximab also improved mucosal healing: Mucosal healing occurred in nearly twice as many patients in the infliximab treatment groups in ACT 1 and 2 at week 8 (62% and 60%, respectively) and week 30 (50% and 46%, respectively) as in the placebo groups at week 8 (34% and 31%, respectively) and week 30 (25% and 30%, respectively). Additionally, infliximab demonstrated early and lasting steroid dose reduction: Patients in ACT 1 had a 75% reduction in their median daily dose of steroids from baseline. Also, nearly 3 times as many patients receiving infliximab 5 mg/kg achieved remission without steroids at week 54 compared with patients who received placebo (26% [18/70] vs 9% [7/79]; P=0.006).

Adalimumab also has been effective in patients with UC.85-87 Adalimumab at doses of 160 and 80 mg has been shown to induce clinical remission in 17% and 9% of patients with UC, respectively, at week 8; additionally, 17% and 9% of patients, respectively, maintained remission at week 52. Mucosal healing was achieved in 25% of patients taking adalimumab compared with 15% of patients on placebo.

The American College of Gastroenterology (ACG) guidelines recommend 5-ASA as first-line therapy for maintenance of remission in patients with UC.88 Among the goals of therapy are the induction and maintenance of remission of UC, and a reduction in the need for long-term corticosteroid use. Steroids are generally reserved for patients who are refractory to 5-ASAs, or for patients with severe UC with systemic illness. AZA and 6-MP are effective for patients who do not respond to steroids and continue to have moderate disease, and who are not acutely ill enough to require IV therapy.

Treatment with IV cyclosporine or colectomy is indicated for patients with severe disease who fail to show significant improvement with 5-ASA, steroids, AZA, or 6-MP, including IV steroids, within 3 to 5 days.

The ACT trials support a role for anti-TNF therapies in the reduction of steroid use and maintenance of remission in patients with UC.84 Approximately 22% of patients who received steroids at baseline had discontinued steroid use by week 30 in both ACT 1 and 2, or by week 54 in ACT 1. When infliximab was administered every 8 weeks, response and remission were maintained at week 30 (53% and 32%, respectively), and at week 54 (45% and 42%, respectively) in patients who had an initial response or remission at week 8 (after 3 infusions of infliximab 5 or 10 mg/kg at weeks 0, 2, and 6).

Along with eliminating the use of steroids and induction of mucosal healing, increasing evidence shows that anti-TNF agents, specifically infliximab, are effective for induction and maintenance of remission in UC. The use

of infliximab is expected to facilitate the widespread use of steroid-sparing therapy for patients with UC, thereby reducing the use of ineffective therapies and improving the quality of care.

Personalizing IBD Therapies In selected patients with moderate to severe UC, an earlier aggressive treatment approach is indicated.13,89 Some patients with mild to moderate disease may benefit from a decrease in medication dosage, adherence to therapeutic regimens, and in some cases, a reevaluation of the diagnosis. Identification of immunologically vulnerable patients through the use of emerging serologic markers, biomarkers, and genotyping may allow for individualized treatment that improves outcomes.

A greater understanding of the human genome is redefining the science of individuality. Less than 0.1% of our DNA is responsible for IBD susceptibility and therapeutic response.90-93 We are at the threshold for genotyping patients and bacteria, which will lead to a greater understanding of the pathobiology of IBD and its treatment.94 Until genomics can be applied to individualized medicine, predicting IBD progression may be achieved through risk assessment, emerging biomarkers, and optimizing mesalamine therapeutic strategies. In selected patients with moderate to severe UC, early intervention with immunosuppressive or biologic therapies—and limited use of steroids—may slow the progression of IBD, and treatment may move from a symptom-oriented, step-up strategy to a preventionoriented, early intervention approach.

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80. Saini SD, Waljee AK, Higgins PD. Cost utility of inflammation-targeted therapy for patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2012 May 18 [Epub ahead of print].

81. Christensen LA, Rasmussen SN, Hansen SH. Disposition of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid in fetal and maternal body fluids during treatment with different 5-aminosalicylic acid preparations. Acta Obstet Gynecol Scand. May 1994;73(5):399-402.

82. Kim TS, Jung KK, Kim SS, et al. Effects of in utero exposure to DI(n-Butyl) phthalate on development of male reproductive tracts in Sprague-Dawley rats. J Toxicol Environ Health A. 2010;73(21-22):1544-1559.

83. Mahadevan U, Martin CF, Sandler RS, et al. PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology. 2012;142(5 suppl 1):S149. Abstract 865.

84. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462-2476.

85. Feagan B, Sandborn W, Yang M, et al. Adalimumab therapy reduces hospitalization and colectomy rates in patients with ulcerative colitis among initial responders. Am J Gastroenterol. 2012;107 (suppl 1):S642-S643.

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I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

90. Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8(6):458-466.

91. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860-921.

92. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291(5507):1304-1351.

93. Jasny BR, Roberts L. Unlocking the genome. Science.

2001;294(5540):81.

94. Kevles D, Hood L, eds. The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge, MA: Harvard University Press; 1992:3-363.

95. Dignass AU, Bokemeyer B, Adamek HE, et al. Maintenance therapy with once-daily 2g mesalazine (Pentasa) treatment improves remission rates in subjects with ulcerative colitis compared to twice daily 1g mesalazine: data from a randomised controlled trial.

Gastroenterology. 2008;134(4 suppl 1):A494. Abstract T1146.

AUTHOR DISCLOSURE—Dr. Scherl has served as a consultant or advisory board member for Abbott Laboratories, AstraZeneca, Axcan Pharma, Berlex, Centocor, Cerimon Pharmaceuticals, Cerium, Crohn’s & Colitis Foundation of America (CCFA), PDL BioPharma, Procter & Gamble, Prometheus Laboratories, Questcor, Salix Pharmaceuticals, Shire, Sigma Tau, Solvay Pharmaceuticals, TAP Pharmaceuticals, and UCB. She has received grants or research support from Abbott Laboratories, Centocor, Cerimon Pharmaceuticals, Elan, Millennium, Osiris Therapeutics, Prometheus Laboratories, Salix Pharmaceuticals, and UCB. She has received honoraria from Abbott Laboratories, AstraZeneca, Axcan Pharma, Centocor, Cerimon Pharmaceuticals, PDL BioPharma, Procter & Gamble, Prometheus Laboratories, Salix Pharmaceuticals, Shire, Sigma Tau, Solvay Pharmaceuticals, TAP Pharmaceuticals, and UCB. She has received other financial or material support from Abbott Laboratories, CCFA, Centocor, PDL BioPharma, Prometheus Laboratories, Salix Pharmaceuticals, and UCB.

MAY 2013 Brought to You by

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REPORT DDW 2013: New Research Improves Monitoring Biologic Therapy for IBD Introduction

remission.1,3 Patients may show an initial response to biologic Increased awareness into William J. Sandborn, MD therapy only to have their IBD the pathophysiology of inflamsymptoms recur. In fact, loss matory bowel disease (IBD) Chief, Division of Gastroenterology of response to biologic therhas led to the development of Director, Inflammatory Bowel Disease Center apy may occur in approximately therapeutic agents that inhibit University of California 50% of initial responders.4 Sevthe proinflammatory cytokines San Diego Health System responsible for these coneral factors have been uncovLa Jolla, California ditions—in particular, tumor ered that collectively affect the necrosis factor-α (TNFα).1 pharmacokinetic and pharmacodynamics profile of biologic Since the FDA’s approval of therapy, including the presence of antidrug antibodies, infliximab (IFX) in 1998,2 several anti-TNFα agents have high baseline levels of TNFα or C-reactive protein (CRP), subsequently been developed for the treatment of Crohn’s high body weight, and concomitant use of immunosupdisease (CD) and ulcerative colitis (UC).3 The use of these pressive agents.3 The influence of antidrug antibodies agents has led to improved outcomes3 and a reduced need for concomitant corticosteroid therapy, an imporon IBD therapy has received increased attention and tant achievement due to the incidence of severe adverse appreciation over the past few years. events and risk for steroid dependence.1 The development of antidrug antibodies can cause hypersensitivity reactions and, more importantly, Although these biologic agents have proven beneficial increased production of these antibodies reduces the in the treatment of IBD, there remain limitations regardefficacy of biologic agents. 3 Antibodies accelerate ing optimal dosing to both induce and maintain disease

Faculty

Supported by

REPORT

clearance of the therapeutic agent and/or negatively effect their binding affinity, thus leading to loss of response and reduced remission rates.3 One study that included 155 patients with IBD who were receiving IFX found that the use of an IFX assay affected treatment decisions in 73% of patients, either by informing the need for dose escalation, switching to another anti-TNFα agent, or discontinuing anti-TNFα therapy.5 Despite the recognition of these interactions, its incorporation into clinical practice has historically been hampered by the absence of assays capable of accurately measuring serum drug concentrations and antidrug antibody levels.3 In the past, clinicians used solid-phase binding types of assays, such as an enzyme-linked immunoassay (ELISA) or electrochemiluminescence immunoassay (ECLIA), to assess serum drug and antibody levels for patients with IBD receiving biologic therapy. However, the utility of these methods is limited because of their inability to accurately detect antibodies

in the presence of anti-TNFα agents due to cross interference.6 Recently, a liquid-phase homogeneous mobility shift assay (HMSA) was developed to measure serum drug and antidrug antibody levels for IFX. New targeted assays may improve the management of IBD by providing unique information about antidrug and antibody levels, an important relationship regarding disease activity and patient outcomes. Assays for measuring IFX and adalimumab antibodies in the presence of serum drug concentrations are now commercially available: PROMETHEUS® Anser™ IFX and PROMETHEUS® Anser™ ADA, respectively (Prometheus Laboratories Inc.). This review features an overview of the latest research on liquid-phase HMSAs and how to interpret serum drug and antidrug antibody levels to help manage patient outcomes in IBD. The abstracts have been accepted and will be presented at the upcoming Digestive Disease Week 2013.

Prevalence of Antibodies to Adalimumab (ATA) and Significance of ATA/ Drug Concentration on CRP and Symptoms in Unselected IBD Patients Fernando S. Velayos, Sarah Sheibani, Steve Lockton, Scott Hauenstein, Sharat Singh, Jonathan P. Terdiman, Uma Mahadevan

ADA-

ADA+

<5 mcg/mL

>5 mcg/mL

Background

10.0

ATA positive

CRP

Detection of antibodies to IFX (ATI) and correlation of serum drug concentration to disease status has provided both insight into immunogenicity and clinical use of these markers in managing IBD patients on IFX. For adalimumab (ADA), such data is not readily available. The detection of antibodies to ADA (ATA) in IBD patients is sparsely reported outside of one companysponsored clinical trial (2.6%). Correlation of ATA and drug concentration with objective markers of inflammation (CRP) and clinical symptoms is not well established in unselected IBD patients.

ATAATA+

Methods An independent investigator-initiated, cross-sectional study prospectively recruited 54 IBD patients on ADA (2 with UC) from a tertiary center to determine 1) prevalence of detectable ATA and drug concentration, 2) correlation of ATA/drug concentration with an objective measure of inflammation, CRP; and 3) whether stratified category of ATA/drug concentration correlated with patient’s self-described symptoms (remission, response, active flare). Patients were approached based on use of ADA for CD or UC and not clinical status (remission, response, active). Questionnaire of symptoms, IBD history, ADA dosing, weight, and CRP measurement were conducted within 2 weeks of ATA/drug concentration measurement.

ATA/drug concentration blood draw was performed at trough, just before next ADA dose, and processed by Prometheus Laboratories. Detectable ATA was defined as ≥1 U/mL and detectable drug as ≥1 mcg/mL.

2

0.1

ATA-

ATA+

ATA-

ATA+

ATA positive Figure. Relationship between ATA, ADA, and disease activity.

ADA, adalimumab; ATA, antibodies to adalimumab; CRP, C-reactive protein

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Results

Conclusion

The prevalence of detectable ATA was 22.2% (n=12/54) and detectable ADA concentration was 90.7% (n=49/54).

Serum concentration of ≥5 mcg/mL of ADA was negatively associated with an elevated CRP (P= 0.001). Detectable ATA was positively associated with an elevated CRP, and notably this correlation was independent of drug concentration (P= 0.002; Figure). Stratification of patients based on ATA/ drug concentration demonstrated more active disease in patients with low drug concentration (<5 mcg/mL) and/or detectable ATA (P= 0.01).

ATA in ADA-treated IBD patients are more prevalent than reported in clinical trials and almost all patients on ADA demonstrate a detectable drug concentration. Both ATA and ADA drug concentration (>5 mcg/mL) appear to have an important role in degree of inflammation. The correlation between ATA with elevated CRP independent of drug concentration is a novel finding and suggests preventing ATA may be the more critical variable to target clinically for efficacy. Correlation between detectable ATA/low drug concentrations with active disease suggests clinical utility to these measurements, however, longer-term data are needed.

Serum Adalimumab Levels and Antibodies Correlate with Endoscopic Intestinal Inflammation and Inflammatory Markers in Patients with Inflammatory Bowel Disease Anders Yarur, Scott Hauenstein, Steven Lockton, Sharat Singh, Maria Abreu

Background ADA is a recombinant monoclonal antibody against TNFα and an effective treatment of CD and UC. Although it is fully human, up to 40% of patients develop antibodies to ADA (ATA), which are associated with lower ADA serum levels and treatment failure. The aim of this study was to assess the degree of correlation of serum ADA and ATA levels with indices of serologic and endoscopic mucosal inflammation in patients with IBD.

Methods We designed a cross-sectional study including patients 18 years or older with CD or UC on treatment with ADA. Predictive variables included were demographics, disease phenotype, concurrent use of immunosuppressive drugs (mercaptopurine, azathioprine, or methotrexate) and/or steroids, and random ATA/ADA levels (measured using a validated non-radiolabeled HMSA by Prometheus Laboratories [San Diego, CA]). The primary outcomes were the presence of macroscopic mucosal inflammation (MMI) during endoscopic exam and CRP level.

Results Sixty-six patients were included: 59 had CD; 62 (94%) and 18 (27%) IBD patients had detectable ADA and ATA,

respectively. A minimum ADA cutpoint of 5 mcg/mL best predicted elevation of CRP levels (ROC, 0.71). The mean ADA level was significantly higher in patients with undetectable ATA than in those with ATA (12.5 vs 5.7 mcg/mL respectively; P=0.001).

Mean ADA levels were higher in patients with mucosal healing than in patients with MMI (13.3 vs 8.5 mcg/mL, respectively; P=0.02). The mean serum CRP level was significantly higher in those patients with detectable ATA than those lacking ATA (12 vs 2.1 mg/dL, respectively; P=0.002). Detectable ATA was associated with ADA <5 mcg/mL (odds ratio [OR], 8.6; 95% confidence interval [CI], 2.3-31.8; P<0.001), MMI (OR, 3.8; 95% CI, 1.1-13.2; P=0.03), need for steroids (OR, 3.7; 95% CI, 1.1-12.9; P=0.03), and previous infliximab use (OR, 3.9; 95% CI, 1.0-15.2; P= 0.04). When compared with those patients prescribed ADA monotherapy, patients combining ADA therapy with an immunomodulator had a higher mean level of ADA (9 vs 14 mcg/mL, respectively; P=0.026).

Conclusions Among patients with IBD, serum ADA and ATA levels correlate well with both serologic and endoscopic inflammatory activity. An ADA level ≥5 mcg/mL correlates well with lower CRP, and combination therapy with immunosuppressive drugs improves serologic levels of ADA. Further work establishing the role of measuring ADA and ATA levels in clinical care are warranted.

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Mechanisms of Loss of Response to Adalimumab in Crohn’s Disease Wolf D, Hauenstein S, Lockton S, Singh S

Background

Results

Anti-TNFα agents, such as ADA, used for the treatment of IBD are effective in reducing disease activity in patients and offer significant benefits in quality of life. Lack of response to ADA is likely due to 3 scenarios: low serum drug levels, antidrug antibody generation, or an alternative mechanism not driven by TNFα. Serum ADA and ATA levels, along with cytokine profiles, were studied in patients with CD who had lost response to ADA treatment to evaluate the mechanism of loss of response.

Forty-two of 49 patients (86%) had detectable ADA (>0.68 mcg/mL) with a median serum concentration of 7.2 mcg/mL and a range of 0.73 to 31.54 mcg/mL, while 23 of 49 patients (47%) had detectable ATA (>0.55 U/mL). Of the 7 patients with undetectable ADA, 6 had detectable ATA, and 17 of the 42 ADA detectable patients were also ATA+ (OR, 0.118; P= 0.041). ADA levels were inversely associated with the level of ATA generation (median ADA for ATA– samples = 9.78 mcg/mL; median ADA for ATA+ samples = 4.9 mcg/mL; P=0.022). Twenty-six of 49 patients (53%) had <8 mcg/mL ADA, a threshold concentration above which has been associated with the best efficacy. Of these patients, 15 had detectable ATA, leaving 11 patients who had subtherapeutic levels of ADA for other reasons. Of the 23 patients with >8 mcg/mL ADA, 8 had detectable ATA (35%). The remaining 15 patients likely lost response due to an alternative mechanism. Several patients demonstrated cytokine profiles that suggest activation of alternative pathways that could be a reason for loss of response.

Methods Approximately 25 sites participated in an institution review board–approved, single-visit study of patients treated with ADA who initially achieved response/remission and experienced loss of response to treatment. Subjects must have been on ADA for ≥3 months and have demonstrated an initial response to ADA as assessed by global assessment or Harvey-Bradshaw Index (HBI). We collected serum samples from 49 patients with CD and tested for serum levels of ATA and ADA using the HMSA as previously described (Wang 2012). Briefly, serum samples and calibrators were mixed and incubated with the labeled antigen. The immune complexes formed and the free label were separated and quantitated by a SEC-HPLC system equipped with a fluorescent detector.

Serum samples were also tested for inflammatory cytokines using proprietary methods.

Conclusions Analysis of ADA and ATA levels in patients losing response showed a high incidence of ATA generation. ADA levels were inversely associated with the level of ATA generation. This study presents evidence that loss of response can result from low drug levels, ATA production, or alternate pathways.

Serum Adalimumab and Immunogenicity in IBD Patients after 80 mg Biweekly Maintenance Therapy Ben-Bassat O, Hauenstein S, Iacono A, Irwin SP, Singh S, Greenberg GR

Background and Aims ADA is effective therapy for CD and UC but maintenance dose escalation from biweekly to more frequent weekly injections may be a requirement to sustain clinical benefit. A more patient-convenient approach of biweekly 80-mg therapy would be an advantage. However, this strategy could be associated with lower trough ADA levels and a higher rate of immunogenicity (ATA) with loss of response. We evaluated the relationship between serum ADA and ATA formation to clinical outcome in IBD patients after dose escalation to 80 mg every other week (EOW) compared with 40 mg every week (EW) using a fluid-phase assay that simultaneously detects drug and ATI.

4

Methods A cohort of 57 patients with IBD (48 CD; 9 UC) were treated with ADA induction followed by maintenance with no escalation of 40 mg EOW (n=13) and dose-escalation to 40 mg EW (n=12) or 80 mg EOW (n=32). Rates of steroid-free clinical remission (HBI ≤2) and normalization of CRP (<5 mg/L) were assessed in relation to the presence or absence of detectable serum levels of ADA with or without ATA formation. Serial serum samples were drawn prior to or at mid-interval of maintenance therapy and concentrations of ADA and ATA measured by an HPLC–based fluid-phase assay (Prometheus Laboratories, San Diego, CA).

Results After a median follow-up of 20.8 months (IQR, 17.1-28.7), rates of steroid-free remission for 80 mg EOW compared with 40 mg EW (75.1% vs 66.6%) were not different (P= 0.81) and

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similar to patients treated with nonescalated 40 mg EOW (69.2%). Median serum ADA for 80 mg EOW compared with 40 mg EW was not different (20.2 mcg/mL vs 19.1 mcg/mL) and tended to be higher than 40 mg EOW (12.5 mcg/mL).

ATA formation for the cohort was 14% and was similar in the 3 groups: 80 mg EOW (12.5%); 40 mg EW (16.6%); 40 mg EOW (15.3%). Median serum ADA for patients in remission (23.8 mcg/mL; IQR, 13.1-27.4) was higher than for treatment failures (4.9 mcg/mL; IQR, 0.8-10.1; P<0.001). The median serum ADA for patients with a CRP <5 compared with CRP >5 was also higher (22.9 mcg/mL vs 10.5 mcg/mL; P<0.001).

Treatment failures had a higher rate of ATA formation (62.5%) and a lower median serum ADA (4.2 mcg/mL; IQR, 0.8-10.3) independent of dose or interval.

Conclusions For patients requiring ADA dose escalation maintenance therapy 80 mg biweekly was as effective as 40 mg weekly with similar serum ADA levels and rates of immunogenicity. Treatment failure was associated with lower serum ADA levels with or without ATA formation and was independent of the dose or interval of maintenance treatment.

Early Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday Baert F, Drobne D, Ballet V, Gils A, Vande Casteele N, Hauenstein S, Singh S, Lockton S, Rutgeerts P, Vermeire S

Background and Aims Pharmacokinetic monitoring enhances understanding and can improve efficacy and safety of anti-TNF therapy. Given the relative paucity of agents and frequent loss of response (LOR) to biologics, we expanded considerably our cohort that restarted IFX after a drug holiday of >6 months and added long-term follow-up. We aimed to identify clinical and biologic predictors (including antibodies to IFX [ATI] and IFX trough levels [TLs]) for success and safety of restarting infliximab in a â&#x20AC;&#x153;high immunogenicâ&#x20AC;? cohort, including patients with prior episodic therapy and patients restarted after LOR or infusion reactions (IR) to IFX in the past.

Materials and Methods We identified a consecutive cohort of 128 patients (105 CD, 23 UC) in whom IFX was restarted after a median drug holiday

of 15 months (range 6-125 months). The reasons why IFX was stopped previously included LOR and/or IR in 29 patients and remission or pregnancy in 99. Serial TL and ATI were determined using an HMSA (Prometheus Labs, Inc.) enabling ATI detection in the presence of TL. We prospectively collected serum samples during first IFX therapy (t-1), at restart (t-0), before the second (t+1), and third infusion (t+2) after restart.

Main outcome was treatment success (clinical and biologic response) and safety (absence of IR). Outcome was correlated to treatment modalities and TL and ATI at all time points.

Results Overall restarting IFX was successful in 84.5% at week 14, 70% at year 1, and in 61% at the end of follow-up (median >4 years). IR occurred in 19.5% (25/128) of whom 10 patients experienced a delayed reaction. In 12.5% (16 pts) IFX was stopped for severity of the IR. The reason for discontinuation of the first course, immunomodulators (IMM) at restart, TL and absence of ATI at t+1 (and t+2) were very significant predictors for response and (absence of) IRs in univariate analysis (Table).

Table. Predictors of Infliximab Success Following Treatment Gap Response

Short term

Year 1

End of follow-up

Infusion reactions

TL t+1 quartiles

IMM

No IMM

IMM

No IMM

IMM

No IMM

IMM

No IMM

TL Q1 (0, 20-0, 36)

91%

37%

73%

25%

55%

0%

9%

88%

TL Q2 (0, 36-5, 23)

93%

75%

60%

75%

53%

50%

33%

25%

TL Q3 (5, 23-17, 34)

91%

78%

82%

78%

91%

56%

0%

11%

TL Q4 (17, 34-41, 22)

100%

100%

80%

100%

80%

100%

0%

0%

TL, trough level; IMM, immunomodulators Note: significant associations in bold

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At multivariate regression analysis the following factors were significant: (1) absence of ATI (hazard ratio [HR], 0.14; 95% CI, 0.026-0.74; P=0.021) and co-treatment with IMM at restart (HR 6; 95% CI, 1.3-27; P= 0.019) for short-term response; (2) reason for discontinuation (pregnancy and/or remission) (HR, 0.37; 95% CI, 0.15-0.92; P= 0.033) and (higher) TLs influenced long-term response (HR, 0.34; 95% CI, 0.13-0.85; P= 0.021); (3) undetectable ATI predicted safe restart (HR for

IR with detectable ATI, 7.7; 95% CI, 1.88-31.3; P= 0.004).

Conclusions Restarting infliximab after a long drug holiday is highly successful short and long term. Higher TL and undetectable ATI titers early after restart predict the outcome very significantly.

IMMs at restart clearly attenuate ATI formation responsible for IRs.

A Multicenter Observational Study in Community Gastroenterology Practices Evaluating the Clinical Usage of Testing for Serum Levels of Infliximab and Antibodies to Infliximab Douglas Wolf, Steven Lockton, Scott Hauenstein, Susan Carroll, Sharat Singh, Emil Chuang

Introduction The purpose of this study is to evaluate the clinical utilization of the PROMETHEUS® Anser™ IFX test for monitoring serum IFX and ATI in patients with IBD on IFX therapy.

This proprietary test uses liquid-phase homogeneous mobility shift technology and has been shown to overcome several of the limitations associated with solid-phase technologies such as ELISA (Wang et al. J Immunol Methods 2012,382:177).

Importantly, with AnserIFX (and unlike solid-phase assays) the presence of serum IFX does not interfere with ATI quantification thus, ATI can be quantified reliably during maintenance therapy.

Methods Patients undergoing IFX therapy were enrolled in the study if the treating physician elected to measure IFX and ATI levels at any time during therapy. Indications for the test, clinical status, and dosing information were collected at the time of blood draw. The physician’s actions, taken in response to the IFX and ATI test results, were documented.

Results As of this analysis, 174 patients (≥18 years) including 115 CD, 56 UC and 3 other IBD were enrolled. Mean age was 38 years, mean BMI was 26.4 kg/m2 and mean duration of disease was 10.3 years. Approximately 40% of the patients were receiving IFX at a dose of 5 mg/kg every 8 weeks and

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fewer than 10% of patients were taking concomitant immunosuppressants. Physician reasons for ordering the test included inadequate or loss of response (38%); the remaining 62% of physicians ordered the test in the absence of a response-related issue. Median IFX concentration was 11.10 mcg/mL and was similar for CD (10.10 mcg/mL) and UC (11.45 mcg/mL). Overall, 32 patients (18.4%) were positive for ATI. These included 23 of 40 (57.5%) who had IFX below threshold (<3 mcg/mL); in comparison, only 9 of 134 (6.7%) who had IFX above threshold (≥3 mcg/mL) were ATI-positive (OR, 0.055; P=3.01 × 10 -11). Actions taken in response to the test results included: 1) changing the IFX regimen in 17 patients; this occurred more frequently in ATI-positive patients (8/32; 25%) than in ATI-negative patients (9/142; 6%; P= 0.011); and 2) switching to another biologic in 4 patients, all of whom were ATI-positive (4/32; 12.5%; P= 0.001).

Conclusions Proportionally more ATI-positive patients had changes in treatment compared with ATI-negative patients. In addition, the findings in this study indicate that ATI development is negatively associated with serum IFX concentrations, consistent with previous reports. When IFX and ATI information from the PROMETHEUS® Anser™ IFX test was given to physicians in community practices, physicians responded by personalizing patient therapy. ATI levels, which other solid-phase technologies do not reliably measure, appear to be especially important in this decision.

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Comparison of Early Measurement of Infliximab and Antibodies-toInfliximab Serum Levels with Standard Trough Analysis Alexander Eser, Walter Reinisch, Scott Hauenstein, Steven Lockton, Sharat Singh

Background With evidence accumulating in favor of the concept of therapeutic drug monitoring, clinicians are increasingly aiming to keep IFX serum levels above certain thresholds. TLs as well as C-max levels have been positively associated with efficacy and negatively with immunogenicity in patients with IBD. Clearance of IFX is increased in the presence of ATI, leading to low serum levels. Here we utilize the HMSA to analyze IFX and ATI levels at mid infusion and trough. Further, we investigate the robustness of HMSA to detect ATI at high serum concentrations of IFX at mid infusion versus TL and compare with ELISA–based data.

Patients and Methods More than 90 consecutive patients with established IBD (Crohn’s disease or ulcerative colitis) under maintenance therapy with IFX were asked to participate. Serum samples were acquired at approximately 4 and 8 weeks post-infusion. Serum levels of IFX and ATI were determined using ELISA (Immundiagnostik) and by HMSA as previously described (Wang et al, 2012). For HMSA, serum samples and calibrators were mixed and incubated with the labeled antigen (IFX or TNFα). The

immune complexes formed and the free label were separated and quantitated by a SEC-HPLC system equipped with a fluorescent detector.

Results Patients were receiving a median dose of 5.51 mg/kg body weight (range 4.08-10.94) IFX yielding a median of 8.98 and 23.0 mcg/mL at trough and mid infusion, respectively. IFX serum levels were significantly higher at mid infusion versus TL (P<0.001). More than 25% of the patients were ATIpositive overall (including mid and trough measurements).

ATI occurred most frequently in patients with nondectable or very low trough levels (77% of patients with <2.31 mcg/mL IFX). HMSA was able to detect ATI at the mid infusion point, while ELISA returned inconclusive results due to interference from IFX.

Conclusions Traditional solid-phase assays (ELISA and ECLIA) experience interference for detecting both IFX and ATI early after infusion. The data presented here demonstrates that HMSA can detect ATI at any point in the infusion cycle, regardless of the amount of circulating IFX. ATI detected at mid infusion is in good agreement with measurement at trough and may provide necessary information for treatment options.

Discussion As these abstracts portend, a new liquid-phase HMSA that can measure ATA in the presence of serum drug concentrations has been developed to help in the management of patients who are losing response to ADA. The abstracts show that a rise in ATA occurs with a parallel increase in CRP levels, thus leading to increased treatment failure and heightened IBD activity (Velayos et al). Moreover, patients with higher serum drug concentrations were observed to have low levels of ATA, and a linear relationship with mucosal healing in patients with CD and UC also was observed (Yarur et al).

Treatment failure with ADA was found to be associated with higher antidrug antibody levels and lower serum drug concentrations (Wolf et al; Ben-Bassat et al).

Likewise, the research on IFX demonstrates a similar trend for patients with IBD. In particular, patients who previously had stopped therapy either due to loss of response or infusion

reactions were able to safely and successfully restart IFX treatment (median holiday of 15 months) when clinicians tailored the dose based on antidrug antibody levels and serum drug concentrations (Baert et al). A multicenter observational study found that clinicians were more likely to alter treatment in patients with IBD and detectable ATI levels (Wolf et al). The final abstract showed that HMSAs were able to detect ATI in the presence of serum drug levels, whereas ELISA and ECLIA led to inconclusive results (Eser et al).

These data shed further light onto the mechanisms behind loss of treatment response and disease remission for patients with IBD receiving biologic agents. With the ability to accurately gauge serum drug and antibody levels for ADA in addition to IFX, clinicians may now be able to offer better personalized care to patients using yet another important biologic agent.

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References 1.

Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011;106(4): 685-698.

4.

Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial. Lancet. 2002;359(9317):1541-1549.

2.

Kornbluth A. Infliximab approved for use in Crohn’s disease: a report on the FDA GI Advisory Committee Conference.

Inflamm Bowel Dis. 1998;4(4):328-329.

5.

Afif W, Loftus EV Jr, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol.

2010;105(5):1133-1139.

3.

Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokineticsbased dosing paradigms. Clin Pharmacol Ther. 2012;91(4): 635-646.

6.

Wang SL, Ohrmund L, Hauenstein S, et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum.

J Immunol Methods. 2012;382(1-2):177-188.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Prometheus, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Disclosures: Dr. Sandborn reported that he has received research support and served as a consultant for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, and Janssen. He has also received research support from Pfizer and Receptos and has served as a consultant for Abbvie, Prometheus Laboratories, and UCB Pharma. He has received honorarium from and served on the speakers’ bureau for Abbvie.