Gastroenterology and Endoscopy News Digital Edition - June 2013 by McMahon Group

1978 —

35th Anniversary — 2013

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The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 6 • June 2013

DDW 2013

Altered Gut Flora Found in Obesity, NAFLD BY DAVID WILD ORLANDO, FLA.—Childhood obesity and pediatric nonalcoholic fatty liver disease (NAFLD) may be associated with altered gut flora and impaired metabolism, according to two new studies presented at the 2013 Digestive Disease Week meeting. Investigators found that the breath concentrations of a host of volatile organic see Gut Flora, page 24

pH Monitoring Could Cut Down PPI Use BY DAVID WILD ORLANDO, FLA.—Almost 30% of patients thought to have gastroesophageal reflux disease (GERD) may be receiving long-term proton pump inhibitors (PPI) unnecessarily, according to a new study presented at the 2013 Digestive Disease Week meeting. Conducting a pH monitoring study immediately following an

Non-Celiac Gluten Sensitivity: Gastrointestinal Hip or Hype? BY BRIGID DUFFY In recent years, “gluten-free” has become a ubiquitous term in the public’s ongoing conversation about what constitutes a healthy diet. From celebrities touting the evils of wheat, to food companies cashing in on gluten-free versions of cookies, Pop-Tarts and donuts, to books and blogs dedicated to the “chic and gluten-free lifestyle,” there is no denying the anti-gluten zeal in American culture. It is therefore no wonder that far more than the approximately 1% of Americans who are diagnosed with celiac disease are swearing off bread, pizza and other staples of American cuisine, all in the name of a self-diagnosed gluten allergy. The recent spike in reported gluten sensitivity leaves a lot of gastroenterologists scratching their heads and asking, “Is non-celiac gluten sensitivity a mere fad, or does the condition warrant more serious consideration?” At the first-ever Intestinal Immune-Based Inflammatory Diseases see Gluten, page 16

see pH Monitoring, page 27

I N S I D E

Gastros Burned Out, but Less So Than Other Physicians

EXPERT ROUNDTABLE Remission in IBD: The Pros and an Cons of Discontinuing Treatment After Remission n .............................................. page 8

BY VICTORIA STERN Gastroenterologists are not immune to the burnout that affects most medical professionals, which is due in large part to an overabundance of bureaucratic tasks and overwhelming work hours. However, compared with physicians in other specialties, the burnout rate among gastroenterologists is comparatively low, according to findings from Medscape’s 2013 physician lifestyle survey.

Miguel D. Regueiro, MD

David T. Rubin, MD Rub

William J. Sandborn, MD

see Burnout, page 30 PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

PRODUCT ANNOUNCEMENT see page 39 for product information

CLINICAL REVIEW IEW see insert between pages ges 20 and d 21

Pancreatic Exocrine Insufficiency Part 2 of 2: Monitoring Clinical Response to Treatment VIVEK KADIYALA, MD SHADEAH LAILA SULEIMAN DARWIN L. CONWEELL, MD, MS Center for Pancreatic Disease Brigham and Women’s Hospital Division of Gastroentero rology, Hepatology, and Endo doscopy Harvard Medical Schooll Boston, Massachusetts

Prometheuss Launches Anser™ ADA Adalimumab Drug and Antibody Level Monitoring Test

Pancreatic Exocrine Insufficiency Part 2 of 2: Monitoring Clinical Response to Treatment

n Part 2 of this 2-part review, monitorin ng clinical response to treatment in patients with pancreatic enzyme insufficiency (PEI) is

covered, as well as future directions in pancreatic enzyme replacement therapy (PERT).

G A S T R O E N T E R O LO GY & E N D O S CO P Y N E WS •

JUNE 2013

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere. 1978 —

35th Anniversary — 2013

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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

tor

Ma Vis it y DD 19- us W 21, bo 2 oth 013 15 31

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, direcof Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................«>}iÊ£È Statins Linked to Reduction in Mortality From Liver Cancer .................................................«>}iÊÓ{

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 Colitis:

Optimizing Mesalamine Strategies 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

ARUN SWAMINATH, MD Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

BRIAN BOSWORTH, MD

see page 63 for product information

he e greatest ch hallenge for 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 at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized approach to the treatment of IBD using 5-aminosalicylic acid (5-ASA) agents.

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

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

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

1978

35th Anniversary — 2 0 1 3

—

The Independ Independent dent Monthly Monthl Newspaper for Gastroenterologists

For more than three decades, Gastroenterology & Endoscopy News has been providing gastroenterology health care professionals with specialty-specific news and reviews, offering comprehensive and objective information for the practicing clinician. 1978 —

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

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

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

Vol. 64, No. 6 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Does ‘X’ Cause Cancer? Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America Philadelphia, Pennsylvania It’s no wonder that the public is confused. Scarcely a month goes by when there is not some report suggesting an association between something we do, eat, breathe or touch and an increased risk for the development of cancer.1 Individuals with even a shallow understanding of the limitations of epidemiologic methodology and the use of statistical analysis in this area will likely appreciate the dangers inherent in any claims that a particular observation suggests a causeand-effect relationship. However, it is uncertain that such understanding characterizes the population at large. It is also well recognized that the results of many such studies are unable to be replicated. Furthermore, results of a subsequently reported “negative” study may have greater difficulty being published in a journal of the same impact factor and almost certainly will generate considerably less interest in the lay press than the initial “positive” association. This concern about suggesting a relationship between some activity and the development of cancer is particularly problematic because this complex

constellation of cancer illnesses generates considerable fear among the public.2 And this fear is likely heightened when there are no known risk factors strongly associated with a particular malignancy or when early detection has not been shown to be an effective strategy to improve the odds for a favorable outcome. Under these conditions, the general public, and specific individuals who believe they are “at risk,” may focus on scientifically questionable reports as a strategy to reduce their own risk for developing the cancer in question. It is reasonable to question whether or not there is any real danger to connecting academic pronouncements in a peer-reviewed manuscript associating “X” cause with “Y” cancer based on a case– control study or a population-based epidemiologic analysis. Furthermore, even if media reports fail to accurately reflect what the paper actually concluded and make a far stronger claim of a possible cause-and-effect relationship than the authors intended, what harm is done? There are several possible answers to this highly relevant question. First, in general, it is likely that these reports do not cause any sustained harm, even if they may cause some confusion. Hopefully, members of an individual patient’s health care team, including primary care providers, will be able to explain the meaning, implications and limitations of reported associations between “X” and cancer “Y” if asked. If questions remain, other

resources (e.g., relevant specialists within the local medical community, the American Cancer Society, the American Society of Clinical Oncology, other specialty societies) should be available to assist. However, in certain circumstances, claimed associations may be more problematic for a particular individual considering the implications of what has been declared as fact. Consider, for example, the statement that certain chemotherapy agents cause secondary malignancies. In this situation, the use of the antineoplastic drugs in question may no longer be employed in routine clinical practice or their schedule may have been substantially changed to reduce or even eliminate the risk.3 Yet, when a paper appears in the literature that describes a relationship like this, the critical fact that the studied strategy is no longer employed in routine clinical practice may not be adequately conveyed in either the paper itself or in media reports. If the outcome among patients is unnecessary fear and an unfortunate decision to stop or not receive clearly documented highly effective therapies, the consequences may be serious, even devastating. In one specific example, it has been suggested that fertility drugs increase a woman’s risk for developing ovarian cancer.4 However, it also is known that infertility itself is associated with a heightened risk for ovarian cancer. Therefore, it is very difficult to differentiate an elevated “baseline” increased risk from any greater risk resulting from the administration of fertility treatments.

And if an individual woman with documented infertility issues is an appropriate candidate for fertility drugs, it is possible that fear resulting from these kinds of reports—which are far from satisfying objective, scientific criteria as definitive— may cause that woman to forgo what for her might be a highly beneficial and lifechanging medical intervention. Of course, it is important to acknowledge here that the public has every right to learn of, and inquire about, the outcomes of research studies that suggest a relationship between any “X” factor and the development of “Y” cancer. But it is essential that the medical and research communities and the lay media make major efforts to clearly explain the objectively valid implications of a study’s findings and the essential limitations of the analysis.

References 1. Schoenfeld JD, Ioannidis JPA. Is everything we eat associated with cancer? A systemic cookbook review. Am J Clin Nutr. 2013;97:127-134. 2. Sontag S. Illness as Metaphor. 1st ed. New York: Farrar, Straus and Giroux; 1978. 3. Kaldor JM, Day NE, Pettersson F, et al. Leukemia following chemotherapy for ovarian cancer. N Engl J Med. 1990;322:1-6. 4. Kurta ML, Moysich KB, Weissfeld JL, et al. Use of fertility drugs and risk of ovarian cancer: results from a U.S.-based casecontrol study. Cancer Epidemiol Biomarkers Prev. 2012;21:1282-1292.

LETTER TO THE EDITOR 1978 —

Doctors Who Treat Patients at ASCs Able To Provide More Efficient Care Re: “Study Shows Owners of Ambulatory Surgery Centers Perform More Surgeries,” by George Ochoa. Gastroenterology & Endoscopy News April 2013;64:42. Your recent article, “Study Shows Owners of Ambulatory Surgery Centers Perform More Surgeries,” makes some good points about the number of advantages that ambulatory surgery centers (ASCs) offer over hospitals when it comes to creating a superior patient and physician experience through innovation and efficiency. Unfortunately, the article also reports findings from a study released by the Workers Compensation Research Institute (WCRI) in May 2012 that the Ambulatory Surgery Center Association and many physicians who choose to treat patients in ASCs find seriously flawed based on the researchers’ capricious assumptions about the 10-year-old data that they used for this analysis (see www.ascassociation.org/ AboutUs/PressRoom/ASCADisputesWCRIReport). Specifically, while the researchers attempt to draw conclusions about the reasons that physician owners of ASCs who provide care to patients inside those ASCs may serve more patients than those who do not,

none of the data used in this study actually identifies which of the physicians represented in the data are ASC owners. Instead, the researchers rely on invalid proxies that are unsupportable and unsound. Furthermore, there is nothing in the data on which the WCRI report is based that indicates the medical necessity of the procedures performed. With such incomplete information, it is difficult to reach any of the conclusions that these researchers are putting forth. The WCRI report referenced in this article also does not consider adequately the reasons why surgeons would choose to treat more patients in a particular setting. As the physician quoted in this article explains, and to which I can personally attest, surgeons who elect to treat their patients in ASCs are routinely able to safely treat more patients in less time than in their local hospitals. Knowing this, it’s no surprise that surgeons working at ASCs would be able to perform more procedures.

— 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Food Allergy Explored in IBS BY CHRISTINA FRANGOU

Defending Against Malpractice: Steps To Winning a Lawsuit Start Before It Beg gins 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

To the Editor:

35th Anniversary

Binge Drinking Linked to IBS Symptoms

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

Additionally, ASCs often offer patients more convenient locations, ease in scheduling surgeries and shorter waiting times. Considering all factors, a more valid conclusion based on the actual data at hand is that surgeons operating in a more efficient setting are able to provide care to a higher number of patients in need, and to deliver a higher quality of care and service to those patients. Thousands of satisfied doctors and patients who have delivered or received care inside ASCs over many decades can attest to this—a fact with far more value than conclusions drawn based on inappropriate proxies and unsubstantiated assumptions. 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).

see Alcohol, page 14

see Malpractice, page 26

EXPERT ROUNDTABLE

I N S I D E

EXPERT REVIEW

Therapy for Barrett’s Esophagus 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

PRODUCT ANNOUNCEMENT

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

Allen Kamrava, MD, MBA

Gary H. Hoffman, MD

CLINICAL REVIEW

see page 45 for product information

see insert between pages 26 and 27

Best of Five MCQs for the Gastroenterology SCE

Pancreatic Exocrine Insufficiency: Part 1 of 2

Now for sale at www.McMahonMedicalBooks.com

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

David Shapiro, MD Immediate Past President Ambulatory Surgery Center Association

Pancreatic Exocrine Insufficiency Part 1 of 2: Treatment Approaches VIVEK KADIYALA, MD SHADEAH LAILA SULEIMAN DARWIN L. CONWEELL, MD, MS Center for Pancreatic Dissease Brigham and Women’s Hospital Division of Gastroenterol ology, Hepatology, and Endo doscopy os Harvard Medical School Boston, Massachusetts

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

CHANCES OF CHATTING ABOUT HER SYMPTOMS ARE PROBABLY LIKE, ZILCH. Ah, IBS. Hearing one symptom per visit is a victory. Last week, abdominal pain. This week, bloating. Next, gas and diarrhea? Despite Rome III Criteria1, there is not an easy way to diagnose her. Dietary management with VSL#3 provides significantly greater improvements in discomfort, bloating and gas2. Recommend VSL#3, a potent probiotic medical food for the dietary management of IBS to your patients. VSL#3 is a medical food and must be used under medical supervision. For further information visit www.vsl3.com 1

“Rome Foundation // Home.” Rome Foundation // Home. N.p., n.d. Web. 19 Mar. 2013. <http://www.romecriteria.org/>. Kim HJ et al. Aliment Pharmacol Ther 17:895-904 (2003).

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

The Pros and Cons of Discontinuing Treatment After Remission Miguel D. Regueiro, MD

David T. Rubin, MD

William J. Sandborn, MD

Professor of Med dicine University of Pittssburgh Medical Center Pittsburgh, Penns sylvania

Professor of Medicine Co-director, Inflammatory Bowel Disease Center Associate Section Chief for Educational Programs University of Chicago Medicine Chicago, Illinois

Professor of Clinical Medicine University of California, San Diego School of Medicine La Jolla, California

COMPILED AND WRITTEN BY MONICA J. SMITH

atients with inflammattory bowel disease (IBD),

who achieve complete remission with therapy, commonly ask whether they

can discontinue one or even both of the treatment agents that helped the em to become well. Gastroenterology & End doscopy News asked three experts in the fie eld how they decide to discontinue or diminish therapy py for patients with Crohn’s Crohn s dise ease ((CD) or ulcerative colitis (UC).

GEN: How do you balance the benefits and risks of therapy for IBD in the long term?

hospitalization, and potentially, if we heal the mucosa, avoid colon cancer. So, although these medicines have risks and side effects, it is my opinion that these medicines are clearly warranted in these patients, and that the benefits far outweigh the small risks.

Dr. Sandborn: The available literature does not support that there is an increased overall risk for serious infection or lymphoma [in patients] on combination therapy with azathioprine or anti–tumor necrosis Dr. Rubin: Despite the fact that one of the most factor (TNF) therapy, relative to either agent alone. common questions we get is “When can I stop my Since combination therapy is more effecdrugs?” we have to remember that for tive than either drug alone, combination ‘Since combination therapy gives the best balance of most patients the safety and efficacy. The excepdisease is chronic and therapy is more effective tions to this are child and teenprogressive. When than either drug alone, aged male patients, who have a greater patients come off risk for hepatosplenic T-cell lymphoma drugs, we’re going to combination therapy gives with combination therapy, and elderly end up with the conthe best balance of safety patients (older than 65 years), who have sequences of recura greater risk for serious infections on rence. What we’ve and efficacy.’ combination therapy. come to appreci—William J. Sandborn, MD ate is something in Dr. Regueiro: I think it depends between: We may on the severity of the IBD. For example, not be able to stop moderate to severe CD and moderate to severe UC most therapies, but we might be able to individualize usually warrant treatment beyond first-line treatment, how much of the therapy they need. The old adage that such as 5-aminosalicylates (5-ASAs). The 5-ASAs whatever you needed to get into remission is what you are considered the “safest IBD treatments,” but may should stay on indefinitely, is being challenged now by be ineffective. In those patients, we need to escalate the concept that when people are in stable remission, treatment to immunomodulators and biologics. Often you may need less intensive therapy to keep them there. the efficacy of those agents is such that we are able to Every time we see a patient with IBD, we should review bring these patients into remission, avoid surgery, avoid the latest evidence, determine whether the medicine

they are on is necessary and working, and assess both the risk of the therapy and the risk of going off the therapy, as well as recurrence of the disease.

GEN: Can you de-escalate therapy after induction of remission, and how do you define “remission”? Dr. Sandborn: The available data on when we can de-escalate therapy in patients in clinical remission on combination therapy is based on observations that are underpowered, and in some instances, uncontrolled. In contrast, large placebo-controlled anti-TNF withdrawal trials of patients who responded to anti-TNF therapy showed that approximately 60% will relapse over the subsequent year. Thus, until large, adequately powered withdrawal trials are done, I do not favor de-escalation in patients receiving combination therapy if they wish to maintain response or remission. Dr. Regueiro: “Remission” is defined in several ways, and the nomenclature has evolved over time. The classic definition of clinical remission has been “patients who have symptomatically improved, or have no or few symptoms.” Most of us define “clinical remission” as a patient who does not require steroids and whose quality of life and physical function is essentially normal. More recently, the term “remission” has evolved to include more objective criteria—specifically mucosal

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

EXPERT ROUNDTABLE

healing—and that has been generally defined by endoscopic or “deep” remission. As far as de-escalating treatment after induction of remission, I think it has more to do with time than induction of remission. If a patient has been in remission for a few months, I would not de-escalate treatment in that patient because I think they would be likely to have recurrent problems. It is my practice to re-evaluate patients one year after they start an immunomodulator and/or an anti-TNF. At that point, I’ll repeat a colonoscopy to ensure that there is mucosal healing. Generally, I do not de-escalate treatment; however, there are some patients whose desire to stop or decrease medications forces our hand. For example, if they are on an anti-TNF and an immunomodulator and they are uncomfortable with taking those medicines long-term, I’ll decrease the w immunomodulator dose or possibly stop it altogether. But patients need to understand that by doing this, they may develop immunogenicity to the anti-TNF and ultimately lose response. Another category of deescalation is in patients whose anti-TNF has been intensified beyond standard doses or treatment intervals. If they’re in a deep remission after a year, we may be able to decrease to the standard interval and standard dose. We should keep in mind that, at present, there are little W evidence-based data on de-escalation.

Dr. Regueiro: Again, I need for surgery from underlying ‘I communicate to patients think it depends on the treatIBD; and that on balance, the ment. For non-biologic medibenefits of continuing combinathat the greatest benefit of cines, if they have worked tion therapy outweigh the risks. treatment is maintenance before, we can usually go back to that medicine again. The Dr. Regueiro: Logistically, of steroid-free remission, biggest challenges are the I do this during my office visit, and that this benefit far monoclonal antibody biologbut also I rely heavily on nurses outweighs the small risk ics: infliximab, adalimumab, and health care extenders to procertolizumab and natalivide education. Also, there are from medications.’ zumab. In patients who stop other great resources, such —Miguel D. Regueiro, MD these medicines and restart as the Crohn’s & Colitis them again at some interval Foundation of Amerin the future, there’s potential ica, that provide excelfor immunogenicity and forlent educational materials and mation of antibodies against these medicines that essen- information on treatments for IBD. From a practical tially renders them ineffective. The patient also may standpoint, I communicate to patients that the greathave allergic reactions and therefore may have to stop est benefit of treatment is maintenance of steroid-free the treatment. However, I do have patients who have remission, and that this benefit far outweighs the small stopped biologics, experienced a flare of symptoms and risk from medications, but we monitor them closely over successfully restarted that same biologic. In these cases, time. Finally, I encourage patients to call if they have it is my opinion that patients take a concomitant immu- questions or if they have concerns about symptoms that nomodulator to limit antibody formation. If they’re may be side effects of treatment. restarting infliximab, I will premedicate each infusion with IV hydrocortisone. Dr. Rubin: This segues from my last comment—that if we’re going to consider withdrawing or reducing treatment, we have to remind patients of two things. First, Dr. Rubin: One of the most imporIBD is not yet medically curable, so it is likely the dis‘Whether we can de-escalate treatment gets tant ways to define “remission” is what ease will progress over time and that they will suffer from to the emerging concept of disease burden— we would consider to be clinical remisw a relapse. And second, we have to remind them what it the amount of inflammation combined with sion, which means that the patient is might take to get their symptoms back under control. feeling well, in addition to some objecWe may need to resort back to steroids because going the amount of intestine that is involved, as tive measure of disease control like healback to a TNF inhibitor may not work. I remind patients well as complications from the inflammation ing of the bowel. The implication of this about the cost of relapsing in terms of their quality of life, is if you’ve achieved that deeper level and how it affects their ability to function socially. This that the patient may have suffered.’ of remission, you may be able to get includes patients who are planning to become pregnant, —David T. Rubin, MD away with a less intensive mainteor who are pregnant and want to be off therapy. The risk nance strategy. That’s why that concept to the developing fetus, if the patient relapses, is quite is tied to this question of de-escalation. significant. So we need to remind patients what it means Whether we can de-escalate treatment if they come off drugs that we otherwise believe are safe. gets to the emerging concept of disease burden—the Dr. Rubin: One of the risks of stopping therapy, or There is a new concept behind this, which is that amount of inflammation combined with the amount of de-escalating it, is relapse, and one of the more impor- we should be thinking about better ways to monitor intestine that is involved, as well as complications from tant questions about relapse is whether a patient is less for early relapse. When a patient is on less intensive the inflammation that the patient may have suffered. likely to respond to treatment if they have been off of it therapy because of a discussion we’ve had or a decision With the concept of disease burden, the idea is that to and then relapsed. For patients with CD, we acknowl- we’ve made, taking a wait-and-see approach is probably induce remission you may need more therapy, and to edge that there is definitely a price to be paid when you wrong in most situations. But incorporating an approach maintain remission you may be able to use appropriate come off therapy because of the progressive nature of where we’re going to take a look early, or use some other but less intensive therapy. The existing evidence, which the disease in most patients. In patients with UC, it’s parameter that will indicate when patients are having is somewhat limited, suggests that in specific populations less clear, but in either case what we know is that when a a recurrence before it happens—when they’re having a we may be able to at least consider dose reduction, and patient relapses, there is a diminished quality of life, and subclinical occurrence before they develop symptoms— possibly in unique situations withdraw one or more treat- it is a lot harder to get a patient back into remission than would hopefully give us information that would enable ments. But it is not a standard of practice yet, and the to have maintained it in the first place. When we talk us to intervene earlier and get them back on track. ■ emerging area of therapeutic monitoring and understand- about withdrawing or reducing any therapies, we’ve got ing individualized pharmacokinetics will enable us to do to remember what it was like when the patient was sick Dr. Regueiro has served as a consultant for AbbVie, Janssen this with objective information rather than guessing. so that we can make a more informed decision about Pharmaceuticals, Inc., and UCB. Dr. Rubin has served as what we’re going to do. a consultant for AbbVie, Elan, Janssen Pharmaceuticals, Inc., Prometheus and UCB, and has received grant support GEN: If you discontinue therapy in a from AbbVie and Elan. Dr. Sandborn has served as a GEN: How do you communicate the risk patient who has stabilized, what happens consultant for and received research support from of stopping or de-escalating therapy to if that patient relapses? Will the patient Janssen Pharmaceuticals, Inc. He also has served as a respond to the same treatments that were an individual patient? consultant for AbbVie and UCB.

already used?

Dr. Sandborn: For the reasons discussed above, I do not discontinue therapy. If patients do discontinue therapy and then relapse, therapy can be reintroduced, but for biologics there will be an increased risk for acute and delayed hypersensitivity reactions and attenuation of response.

Dr. Sandborn: I tell patients that the most risky medication they will take is prednisone; that there are not significant differences in the risks for serious infection and lymphoma between azathioprine monotherapy, anti-TNF monotherapy and combination therapy (except in young males and elderly patients); that there is an increased risk for serious infection and also the

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Biologic Switch Should Be Last Resort For Loss of Response to Anti-TNFs BY DAVID WILD HOLLYWOOD, FLA.—Loss of response to an anti–tumor necrosis factor (TNF) agent should not prompt an immediate switch to another biologic. Moving to another biologic should be the last option because the likelihood of a renewed and

sustained response decreases with each successive biologic switch, according to Gary Lichtenstein, MD, professor of medicine, Division of Gastroenterology, and director of the Center for Inflammatory Bowel Disease, both at the Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia. The question of whether and when to

switch to a second or third biologic is sig-nificant given that 77% of patients with h Crohn’s disease (CD) lose response too infliximab (Remicade, Centocor Orthoo Biotech) within two years of startingg treatment (Wu EQ et al. Value Healthh 2008;11:820-829). Dr. Lichtenstein spoke on the subjectt at last year’s Advances in Inflammatoryy

‘Many patients quickly lose response after switching to another biologic and some also develop adverse events.’ —Gary Lichtenstein, MD

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Bowel Diseases, Crohn’s & Colitis Foundation’s Clinical & Research Conference, where he urged clinicians to first rule out disease complications that may be causing symptoms, to minimize potentially disease-aggravating environmental factors or to intensify the dosage of treatment. “Many patients quickly lose response after switching to another biologic and some also develop adverse events,” Dr. Lichtenstein said, adding that results from the GAIN trial have demonstrated this point (Sandborn WJ et al. Ann Intern Medd 2007;146:829-838). In that study, 325 patients with moderate to severe CD who had lost response to infliximab were randomized to receive either adalimumab (Humira, Abbott) or placebo. Of the 159 patients who received an induction dose of adalimumab, 21% achieved remission and 52% achieved response. Switching to a third drug may reduce further the chance of achieving a sustained response, while also heightening the risk for adverse events, Dr. Lichtenstein said. In one study, 67 patients with CD who had lost response to two prior anti-TNF agents were administered either adalimumab or certolizumab (Cimzia, UCB) (Allez M et al. Aliment Pharmacol Ther 2010;31:92-101). After a median followup of 26 weeks, 36 patients had discontinued the drug—13 due to intolerance and 23 due to lack of response. “These data suggest that before switching to another biologic, we should be evaluating our patients for disease complications, enteric infections and other variables that might be managed, as well

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

‘The best approach to loss of response is to prevent it. Always consider a loading dose; avoid episodic dosing; consider using a concomitant immunomodulator; administer pre-infusion hydrocortisone in infliximab recipients; and encourage Crohn’s disease patients to stop smoking.’ —William Sandborn, MD as using dose intensification strategies,” Dr. Lichtenstein said. Some symptoms are related to disease complications that require surgical instead of medical treatment, he said. These include fibrostenotic disease, intraabdominal and pelvic abscesses, and toxic megacolon. Similarly, bacterial infections—such as Clostridium difficile— e parasitic diseases and cytomegalovirus can mimic IBD symptoms, and patients should be examined for these and treated before switching biologics. Dr. Lichtenstein said that patients also should be evaluated for the use of nonsteroidal anti-inflammatory drugs, cigarette smoking and poor medication adherence because these can cause symptoms and should be controlled as much as possible. Once other potential causes have been evaluated and addressed, clinicians should consider increasing the dose of the anti-TNF medication. Data from the ACCENT 1 and 2 trials of infliximab support this strategy (Hanauer SB et al. Lancett 2002;359:1541-1549; Sands BE et al. N Engl J Medd 2004;350:876885). In those studies, 89.3% and 57.1% of a subset of patients in the two trials, respectively, who had lost response were able to regain response after the dose of infliximab was raised from 5 to 10 mg/kg. Shortening the dosing interval is another strategy for increasing the dosage of drug, according to Dr. Lichtenstein. He pointed to results from a study of 33 infliximab recipients and 14 adalimumab-treated patients who had their dosing intervals shortened following a

l of response (Lukas M et al. Digestive loss Disease Week [DDW] 2011; abstract D Mo1239). Sixty-seven percent of inflixM iimab recipients and 36% of adalimumab rrecipients regained response, and approxiimately half of these patients were able to rreturn to a normal dosing schedule. A retrospective analysis of 40 patients with IBD who lost response to infliximab w aand had their dosing interval shortened oor their dose increased, or underwent both measures, also supported the potenb ttial efficacy of this strategy (Parlente B et aal. DDW Sa1306). In that study, 70% of

NEW

patients regained response following dosing interval abbreviation. “The best approach to loss of response is to prevent it,” said William Sandborn, MD, chief of the Division of Gastroenterology at the University of California, San Diego, in La Jolla. “Always consider a loading dose; avoid episodic dosing; consider using a concomitant immunomodulator; administer pre-infusion hydrocortisone in infliximab recipients; and encourage Crohn’s disease patients to stop smoking.” Dr. Sandborn said that although

dose intensification may be an effective way of regaining response, durability of the renewed clinical response remains unknown, and clinical trials on the topic are needed. ■ Dr. Lichtenstein has received research funding, served as an advisory board member or received honoraria from Abbott Laboratories, Janssen Pharmaceuticals and UCB. Dr. Sandborn has served as a consultant for UCB, and has received consulting fees and research support from Abbott and Janssen.

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)

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

FDA Approves New TNF Inhibitor, Golimumab, for Ulcerative Colitis BY MONICA J. SMITH Golimumab, a tumor necrosis factor (TNF) inhibitor previously approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis and ankylosing spondylitis, was approved for a new indication on May 15—the treatment of moderate to severe ulcerative colitis (UC) in adults. The FDA approved golimumab,

marketed under the brand name Simponi by Janssen Ortho Biotech, Inc., for adult patients with moderate to severe UC that is resistant to prior treatments or that requires continuous steroid therapy. The approval was based on two clinical studies of golimumab that evaluated safety and efficacy of the drug. William Sandborn, MD, professor of medicine, University of California, San Diego, in La Jolla, presented findings

from investigational studies at last year’s Digestive Disease Week meeting and the American College of Gastroenterology’s (ACG) annual meeting. “At [DDW 2012], we reported that 400 mg/200 mg, and 200 mg/100 mg of golimumab, administered at weeks 0 and 2, respectively, were effective at achieving clinical response, clinical remission and mucosal healing in patients with moderate to severe UC.” Those patients were anti-TNF-naive

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

and had failed steroids or immunosuppressive agents (see “New Anti-TNF, Golimumab, Effective in Moderate to Severe UC,” by David Wild. Gastroenterology & Endoscopy News July 2012;63:12,16). At the ACG meeting, Dr. Sandborn presented data on 464 patients who responded to induction therapy with golimumab and were then randomized to receive golimumab at 50 or 100 mg, or placebo, every four weeks through week 52. Patient characteristics and disease status were similar to those in the induction trial: About half the patients were male, with a median age in the mid-30s; median disease duration was about 4.5 years; and 44% of patients had extensive disease. About 80% of patients were taking 5-aminosalicylic acid (5-ASA); half were taking corticosteroids; and 32% were taking azathioprine or 6-mercaptopurine. At week 52, clinical response was seen in 47% of patients receiving the 50-mg dose of golimumab and in 51% of those receiving the 100-mg dose compared with 31% in the placebo group ((P=0.01 and P<0.001, respectively). At weeks 30 and 54, clinical remission was seen in 24% of patients in the 50-mg dose group, 29% of the 100-mg dose group and 15% of the placebo group, and mucosal healing was seen in 42%, 44% and 27% of patients, respectively. Corticosteroidfree remission was observed in 28% and 23% of the two treatment groups and in 18% of the placebo group, but these differences were not significant. “We demonstrated that among patients who responded to induction therapy at week 6, golimumab 50 or 100 mg every four weeks was more effective than placebo for maintaining clinical remission, clinical response and mucosal healing at week 54,” Dr. Sandborn said. “In terms of safety … overall infection rates were higher in the golimumab group; however, serious infections and discontinuations due to adverse events were relatively similar,” Dr. Sandborn said. A few adverse events were notable in the golimumab group, including three deaths from cardiac failure, malnutrition and sepsis, and disseminated tuberculosis. Malignancy rates were similar in the treatment and placebo groups. In its approval of golimumab, the FDA cited the most common side effects of the drug as upper respiratory infection and redness at the site of injection, as well as an increased

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Adverse Events Associated With IBD Therapy May Not Warrant Treatment Cessation BY DAVID WILD HOLLYWOOD, FLA.—Some experts in inflammatory bowel disease (IBD) believe too many physicians discontinue the use of immunomodulators in patients who experience adverse events (AEs). “Each patient needs to be individualized, and I cannot say there is one standard approach for all adverse events, but for most adverse events, we probably do not need to stop our biologics and immunomodulators,” said Miguel Regueiro, MD, professor of medicine and co-director of the Inflammatory Bowel Disease Center in the Division of Gastroenterology, Hepatology, and Nutrition at the University of Pittsburgh. “And if we do stop, we can probably restart them at some point in the future,” he added, speaking to attendees of last year’s Advances in Inflammatory Bowel Diseases, Crohn’s & Colitis Foundation Clinical & Research Conference. Some clinicians may suffer from “kneejerk” switches to other agents if infusion- or injection-site reactions occur, but Dr. Regueiro said these are among the more manageable AEs related to anti–tumor necrosis factor (TNF) drugs, and premedication can be used to prevent such reactions.

Infections Treatment-related infections also do not typically warrant complete treatment cessation, Dr. Regueiro said. The case of a 33-year-old patient with severe Crohn’s disease (CD) receiving infliximab (IFX) and azathioprine (AZA) is illustrative: The patient presented with a cough, myalgia, weight loss and low-grade fever, all of which had been present for one month. Thorough testing revealed histoplasmosis. According to Dr. Regueiro, in a case like this, physicians need to weigh the risk for relapse associated with complete treatment cessation against the possibility for further treatment-related infections. Because most patients are not at significant risk for relapse if treatment is paused for up to several months, Dr. Regueiro recommended withholding both AZA and IFX during months 1 to 3

risk for developing serious infections, invasive fungal infections, reactivation of hepatitis B virus infection,

while the infection is treated. “Once the histoplasmosis has cleared, you can restart treatment and, from my experience, the patient will not get a reinfection,” he said. Tuberculosis (TB) can be managed most easily through early detection and pretreatment screening. If screening reveals latent TB, anti-TNF therapy can be initiated three to four weeks after starting isoniazid treatment. If active TB is found before anti-TNF initiation, it is advisable to wait two to three months after TB treatment is initiated before starting anti-TNF therapy. In patients with TB that emerges during anti-TNF therapy, the anti-TNF treatment should be paused and then resumed two months after TB treatment is initiated, said Dr. Regueiro. “A good rule of thumb is to work with

my feeling is that we probably should not stop treatment while clearing the infection,” he said.

Cancers Lymphoma, a particularly feared complication of immunosuppression therapy, may not require complete treatment discontinuation. “Again, there are not enough data, and I think it behooves us to hold treatment, but in my own experience with a patient with non-Hodgkin lymphoma, the patient did well with lymphoma treatment and was able to restart anti-TNF therapy.” Most patients with a previous history of lymphoma can be administered thiopurine and anti-TNF treatment if the cancer has been inactive for at least one year. However, “it is imperative to work directly with

‘Each patient needs to be individualized, and I cannot say there is one standard approach for all adverse events, but for most adverse events, we probably do not need to stop our biologics and immunomodulators.’ —Miguel Regueiro, MD your infectious disease specialist with any opportunistic infection in IBD,” he said. Both 6-mercaptopurine (6-MP) and AZA carry an increased risk for infections, including herpes zoster (shingles) and other opportunistic infections. “Most episodes of shingles are self-limited, and IBD medications do not need to be discontinued,” Dr. Regueiro said. “If a patient has active zoster vesicles, I’ll usually hold immunosuppression for a week or two until the lesions crust over.” Regarding Clostridium difficilee infection, Dr. Regueiro noted that it is not known whether it is necessary to stop immunosuppression in the presence of infection, highlighting the elusive nature of a “correct” treatment decision in this case. “But since C. difficilee can worsen IBD,

the oncologist to make treatment decisions,” and to provide multidisciplinary care, Dr. Regueiro said. A multidisciplinary team also is crucial for patients on long-term immunosuppression and should include skin cancer screening by a dermatologist. These cancers are increasing in incidence “at an alarming rate” in the general population, and thiopurines and anti-TNF agents further raise the risk, Dr. Regueiro said, citing a 2011 study (Peyrin-Biroulet L et al. Gastroenterologyy 2011;141:1621-1628). Despite the associated risk, “it is rare that you need to stop all immunosuppression if skin cancer occurs.” “If the basal or squamous cells are removed and monitored by a dermatologist, I do not stop immunosuppression,”

lymphoma, heart failure, nervous system disorders and allergic reactions. Sunanda Kane, MD, professor of medicine at Mayo Clinic, Rochester, Minn., noted that because golimumab, the fourth anti-TNF agent to be used for treatment of inflammatory bowel

disease, is administered intravenously, it does not offer patients convenience over adalimumab injection (Humira, Abbott), which was approved by the FDA last September for the treatment of UC. “It is unclear where golimumab may fit in the treatment algorithm for steroid-dependent patients with UC, but

Dr. Regueiro said. “If a patient has escalating numbers of cancer cells, I decrease the dose, or switch from combination immunosuppression to monotherapy.” In contrast to the ambiguity and caseby-case nature of treatment decision making in many situations, the treatment decision is unequivocal if hepatosplenic T-cell lymphoma emerges, Dr. Regueiro said. “In this case, you should stop all immunosuppressant treatments.”

Other AEs Anti-TNF–related psoriasis is rare, but common enough that clinicians should be able to recognize its various phenotypes. The most common type is not the typical extensor surface skin lesions, but palmoplantar pustular psoriasis and psoriasiform lesions that involve the scalp, trunk and flexure regions, Dr. Regueiro said (Cullen G et al. Aliment Pharmacol Therr 2011;34:1318-1327). Milder psoriasis often responds to topical treatment or methotrexate and does not require antiTNF discontinuation, but severe cases may warrant switching to another anti-TNF or discontinuing the treatment altogether. “When in doubt, refer these patients to a dermatologist,” Dr. Regueiro said. Corey Siegel, MD, director, Inflammatory Bowel Disease Center, DartmouthHitchcock Medical Center, Lebanon, N.H., said that physicians sometimes discontinue treatment due to symptoms that may not be side effects at all and are mistakenly attributed to the medication or are manageable with simple strategies. “However, more serious side effects like pancreatitis, which occurs approximately 3% of the time, should always lead to drug discontinuation,” Dr. Siegel said. “More common and mild adverse effects can be easily controlled, for example, by changing a medication dose; the timing of administration; or premedication or coadministration of an antiemetic if nausea occurs.” ■ Dr. Regueiro has served as a consultant for AbbVie, Janssen Pharmaceuticals and UCB. Dr. Siegel has received speaking fees and grant support from AbbVie and Janssen Pharmaceuticals, and is a consultant and advisory board member for both companies; he also has received grant support from UCB.

it is yet another choice for clinicians and patients,” she said. —Additional reporting by Cynthia J. Gordon, PhD Dr. Sandborn is an investigator for Janssen R&D, LLC. Dr. Kane reported no relevant conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Gluten continued from page 1

Symposium held at Columbia University Medical Center in March, a host of physicians, scientists, nutritionists and other clinicians from Columbia University Medical Center and Weill Cornell Medical College, both in New York City, addressed the growing prevalence of nonceliac gluten sensitivity and shared methods by which doctors can diagnose and treat patients who claim, “I just can’t eat wheat.”

Three Types of Gluten-related Autoimmune Conditions In a lecture entitled, “Celiac Disease vs. Gluten Sensitivity: How Common?” Peter Green, MD, director of the Celiac Disease Center at Columbia University, explained that although there is a spectrum of gluten-related disorders with different definitions and proliferations of guidelines, specialists typically place gluten-related autoimmune conditions into three categories: wheat allergy, celiac disease and non-celiac gluten sensitivity. Wheat allergy is mainly a pediatric disorder that tends to peak and then subside by the age of 1 year. However, there are an increasing number of cases of exerciseinduced wheat allergy among nonpediatric patients, as well as cases of contact urticaria among food handlers, bakers and restaurant personnel who are in frequent contact with uncooked wheat. Although some specialists are baffled by the recent rise in wheat allergy, some speculate that it is because wheat grown today contains higher levels of gluten, as it helps to provide the sticky, chewy texture desirable in bread and baked goods. Blame it on the bagel. The second and perhaps most well-known category of gluten-related autoimmune conditions is celiac disease, which affects roughly 1% of people worldwide, with children, adults and the elderly among them. People with celiac disease have one or two genetic mutations that cause the immune system to attack the walls of the intestine as gliadin proteins travel through the gastrointestinal tract. That, in turn, causes the finger-like villi that absorb

nutrients in the small bowel to atrophy, rendering the intestine permeable. Dr. Green noted that like wheat allergy, the incidence of celiac disease has increased over the past 50 years, a phenomenon that continues to bewilder specialists in the field. Notably, many of these cases remain undiagnosed. According to a 2012 study, about 0.7% of the individuals who participated in the National Health and Nutrition Examination Survey 2009-2010 tested positive for celiac disease, but of that group, only 17% were aware that they had celiac disease (Rubio-Tapia A et al. Am J Gastroenteroll 2012;107:1538-1544). The vast majority of individuals with celiac disease could be consuming gluten, putting them at a greater risk for complications, including mortality. The same report found that nearly an equivalent number of people—roughly 0.6% of the U.S. population—followed a gluten-free diet but did not have celiac disease (see “Growing Market in Gluten-Free Foods Does Not Match Prevalence of Gluten Sensitivity,” below). Specialists generally have treated the third category of gluten-related disorders, described as non-celiac gluten sensitivity, with some degree of skepticism over the past several years. Even the definition of the category is less of a diagnosis than it is a catchall description: patients who do not have wheat allergy or celiac disease, but whose health appears to improve in response to a glutenfree diet. Further frustrating specialists is the conditions’ myriad symptoms that manifest differently from patient to patient, leading some specialists to believe that there is more than one type of illness at play. Initially, Dr. Green had some degree of confusion about the illusive non-celiac gluten sensitivity. “Seeing all these patients, I didn’t really know what it was. I found it very hard to grasp hold of this condition in which patients, when you tested them, were normal, but some had this profound effect [when they were] off gluten. I just didn’t understand it.” Many specialists have asked themselves: Is gluten sensitivity all in patients’ heads? Views started to shift when The American Journal of Gastroenterologyy published a 2011 study led by Peter

Gibson, MD, at the Eastern Health Clinical School in Melbourne, Australia. In this double-blind study of 34 patients, those who suffered from irritable bowel syndrome (IBS), did not have celiac disease and were on a gluten-free diet were given bread and muffins to eat for up to six weeks. Some of the participants were given gluten-free bread and muffins, whereas others got baked goods and bread containing gluten. Those who ate the gluten-based products reported that they suffered significantly worse abdominal pain, bloating, fatigue, nausea and gas. In these patients with IBS, it appeared that a gluten-free diet was much more than a placebo effect. “While it’s nowhere near as common as we thought, it’s an iceberg phenomenon, and IBS is a very big part of the iceberg,” Dr. Green said.

Diagnosing Patients There are up to 130 different symptoms associated with gluten sensitivity, and virtually every tissue in the body can be affected, which makes the prospect

Growing Market in Gluten-Free Foods Does Not Match Prevalence of Gluten Sensitivity BY TED BOSWORTH LAS VEGAS—The reported growth in the market for gluten-free foods is difficult to understand in the context of recent estimates of the prevalence of gluten sensitivity, according to reports. In one food industry report, the annual market for gluten-free foods in the United States was placed at more than $4 billion. Yet, gluten sensitivity, including celiac disease and other causes, is estimated to affect less than 2% of the U.S. population. The increase in marketing for gluten-free foods has increased awareness of gluten hypersensitivity, but a team of Columbia University investigators who presented data at last year’s annual meeting of the American College of Gastroenterology (ACG) was unable to detect a corresponding increase in the prevalence of problems with gluten digestion. Although there is some evidence that the prevalence of celiac disease is increasing, one recent estimate reported a prevalence of only 0.71%

(Rubio-Tapia A et al. Am J Gastroenterol 2012;107:1538-1544). The relatively low incidence of celiac disease “leads to the inference” that the large increase in the market for gluten-free products is being driven by gluten sensitivity among people without celiac disease, reported Daniel V. DiGiacomo, MPH, and Peter H. Green, MD, researchers at Columbia University College of Physicians and Surgeons who presented the data at the ACG meeting. However, the article by Rubio-Tapia et al, which was based on data from the National Health and Nutrition Examination Survey 2009-2010, found that non-celiac gluten sensitivity remains uncommon, and that “most persons who were following a gluten-free diet did not have a diagnosis of celiac disease.” “The estimated prevalence of non-celiac gluten sensitivity in the United States is 0.55%, which is approximately half that of celiac disease,” reported the investigators of the ACG study. With both figures combined, the prevalence of gluten hypersensitivity would be less than 2%, or no more than 7 million individuals. Therefore, each of these individuals would need to spend an average of more than $500 per year

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Wheat grown today contains higher levels of gluten, which helps to provide the sticky, chewy texture desirable in bread and baked goods. Blame it on the bagel. of successfully diagnosing a patient’s condition all the more difficult for gastroenterologists. But although experts do not yet know the mechanism behind gluten sensitivity, there are some steps that doctors should keep in mind when dealing with patients who think they have a wheat allergy. Christina Tennyson, MD, assistant professor of clinical medicine at Columbia University noted that the most important step when treating a patient with suspected gluten sensitivity is to rule out celiac disease. Patients with celiac disease have an increased risk for neurologic problems and certain cancers compared with patients with non-celiac gluten sensitivity, which makes diagnosing the disease all the more critical. After establishing if a patient is on a gluten-free diet, the tissue transglutaminase (tTG) immunoglobulin (Ig) A antibody test is the single best test to determine if a patient has celiac disease. Although in theory the test is only revealing if the patient is presently eating gluten, Dr. Tennyson noted that in most patients with celiac disease,

tTG antibody levels usually return to normal within six to twelve months. Therefore, it is often still worthwhile to screen even patients who are following a gluten-free diet. After celiac disease has been ruled out, patients should be directed to a dietitian and followed over time. Dr. Tennyson noted that long-term checkups are crucial because many patients initially respond to a gluten-free diet, but may find that symptoms come back over time. Specialists also should keep in mind that the culprit is not always gluten. Dr. Green stressed that there is always a possibility that other allergies are at play. “When we see these patients, we often find something else that accounts for these symptoms, like bacterial overgrowth, or fructose intolerance,” he said. “It’s worthwhile evaluating these patients because sometimes you can offer an alternative diagnosis and they can go back to eating gluten.”

Treating Patients A common theme throughout many of the presentations at the symposium was the issue of “gluten contamination.” Even the most conscientious of patients who follow a gluten-free diet may be unknowingly ingesting the prohibited protein composite. In 2002, researchers from Mayo Clinic, Rochester, Minn., reported that gluten contamination is the single biggest culprit in patients who have a poor response to a gluten-free diet (Abdulkarim AS et al. Am J Gastroenterol 2002;97:2016-2021). One of the chief reasons is that an increasing number of food manufacturers and fast-food companies are using microbial tTG, or “meat glue,” as a means to cross-link proteins and give processed meat its desired shape. Even products as seemingly innocuous as turkey bacon might contain this gluten trigger. Moreover, the FDA does not require food companies to list tTG on its labels because the agent is considered a “processing aid.” In these cases, even patients with celiac disease or gluten sensitivity who are the most committed to a gluten-free diet don’t stand a chance. Considering that 7% to 30% of patients report continued symptoms when maintaining a gluten-free diet and many more patients find it extremely difficult to

adhere to a gluten-free diet, some specialists are seeking out nondietary therapies for patients. In her presentation, “Non-Dietary Treatment of Celiac Disease, Fact or Fiction,” Dr. Tennyson noted that many patients with celiac disease are aching for an alternative, and although experts do not yet know enough about non-celiac gluten-sensitive patients, some of these therapies might be available to them as well. A few methods involve ways to minimize gluten exposure in the small intestine. For example, there is increasing potential to genetically modify different varieties of wheat to contain lower amounts of the immune-stimulating prolamin proteins—good news for patients who prefer non-chewy bread to no bread at all. Additionally, recent studies have shown promise for an enzymatic oral supplement that promotes gluten degradation in the stomach before it reaches the small intestine where it can cause damage. Another breakthrough in celiac disease therapy is a new medication called larazotide (Alba Therapeutics), a first-in-class oral peptide. This protein targets the junctions of intestinal cells and has been shown to prevent gluten entry into the lamina propria. Last year, Daniel Leffler, MD, of Beth Israel Deaconess Medical Center in Boston, and his colleagues published a randomized, double-blind study of larazotide (Am ( J Gastroenterol 2012;107:1554-1562). The researchers showed that some lower doses of larazotide acetate reduced gluteninduced immune reactivity and symptoms in patients with celiac disease undergoing a gluten challenge and was generally well tolerated. Other researchers are studying ways to reduce immune activation with the use of probiotics or vaccines that target tTG inhibition, the modulation of cytokine secretion or the blockage of HLA DQ2 and DQ8 serotypes. Although many of these new therapies will be welcome news for patients with celiac disease and gluten sensitivity, for many doctors, figuring out why celiac disease and gluten sensitivity are on the rise is often the most baffling aspect of gluten-related autoimmune diseases. As Dr. Green noted in his final remarks, “There’s so much more to learn.” ■

“Future studies are merited in order to understand the true population burden of non-celiac gluten sensitivity,” the authors suggested. Asked to comment, Rupa Mukherjee, MD, of the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, reported that the disparity between the prevalence of celiac disease and the growth in gluten-free foods has attracted her attention. She cited a report from Reuters that predicted the gluten-free market would grow another 22% by 2015. “Those with celiac disease, non-celiac gluten sensitivity and ‘Those with celiac disease, non-celiac gluten sensitivity and gluten- gluten-sensitive irritable bowel syndrome are unlikely to account for this degree of consumption,” said Dr. Mukherjee, who recently sensitive irritable bowel syndrome are unlikely to account for this authored a review article on nondietary therapies for celiac disease degree of [gluten-free] consumption.’ (Gastrointest Endosc Clin N Am 2012;22:811-831). —Rupa Mukherjee, MD “There is certainly substantial public interest in the gluten-free diet, which is likely fueling … consumption by patients with gluten on gluten-free products in order to sustain a $4 billion market. Conse- hypersensitivity. Further data on the use of a gluten-free diet among the quently, it appears likely that either non-celiac gluten sensitivity is being general public would be revealing.” underestimated, or gluten-free food marketing appeals to individuals without gluten sensitivity. Drs. DiGiacomo, Green and Mukherjee reported no conflicts of interest.

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

Commonly Prescribed Antihypertensive Drug Linked To Sprue-Like Enteropathy in Some Patients BY MONICA J. SMITH A topic of conversation at this yearâ&#x20AC;&#x2122;s Digestive Disease Week meeting, olmesartan medoxomil (Benicar, DaiichiSankyo), a commonly prescribed blood pressure medication, has been reported to cause severe, sprue-like enteropathy in some patients. One of seven angiotensin receptor blockers approved by the FDA, olmesartan is unique because its prodrug activity occurs in the small bowel. Margot Herman, MD, of the Department of Medicine, Mayo Clinic, Rochester, Minn., presented a case of a 59-year-old patient, with a history of hypertension, who came in for a second opinion after struggling for a year with severe diarrhea and weight loss at last yearâ&#x20AC;&#x2122;s American College of Gastroenterology (ACG) annual meeting.

of those patients were taking olmesartan. â&#x20AC;&#x153;At that point, we asked our patients to change their blood pressure medication,â&#x20AC;? Dr. Herman said. â&#x20AC;&#x153;These patients improved inexplicably.â&#x20AC;? The patients included 13 women, with a median age of 69 years, most of whom were taking up to 40 mg per day of olmesartan. They were experiencing severe and

protracted diarrhea with a mean duration of 19.2 months. Weight loss was common, and in many cases patients lost up to half of their body weight; most of them required hospitalization for dehydration and other symptoms. The most significant symptom was the change in small bowel histology. All of the patients had villous atrophy; 15 had

total villous atrophy and seven had subepithelial collagen deposition. Laboratory results did not indicate celiac disease, and gluten-free diets and systemic steroids were ineffective in treating these patients. However, once the patients were taken off olmesartan, all had complete resolution of diarrhea and required no further therapies. Many were able to gain weight,

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

â&#x20AC;&#x2DC;I definitely believe this drugâ&#x20AC;&#x201D;and I donâ&#x20AC;&#x2122;t know howâ&#x20AC;&#x201D;is causing a problem.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Sheila E. Crowe, MD INDICATIONS AND USAGE UCERISâ&#x201E;˘ is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. DOSAGE AND ADMINISTRATION The recommended dosage of UCERIS is one 9-mg tablet to be taken once daily in the morning with or without food for up to 8 weeks.

IMPORTANT SAFETY INFORMATION â&#x20AC;&#x153;She had total villous atrophy in her small bowel that had been refractory to all treatments for sprue. She was on [total parenteral nutrition] and was desperate for an answer,â&#x20AC;? Dr. Herman said. The patient asked if her symptoms could be due to her blood pressure medication, which seemed unlikely, as she had been taking olmesartan for more than a year before the onset of her symptoms, Dr. Herman said. But that same week another patient asked a similar question, prompting Mayo researchers to look back at a cohort of 22 patients with collagenous sprue. The researchers found about 30%

CONTRAINDICATIONS UCERIS is contraindicated in patients with known hypersensitivity to budesonide or any of the ingredients of UCERIS. WARNINGS AND PRECAUTIONS t )ZQFSDPSUJDJTN BOE BESFOBM TVQQSFTTJPO 4JODF 6$&3*4 JT B glucocorticosteroid, general warnings concerning glucocorticoids should be followed. t 5SBOTGFSSJOH QBUJFOUT GSPN TZTUFNJD DPSUJDPTUFSPJET Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS. t *NNVOPTVQQSFTTJPO 1PUFOUJBM XPSTFOJOH PG JOGFDUJPOT FH existing tuberculosis, fungal, bacterial, viral, or parasitic

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 function affects the elimination of glucocorticosteroids. t 0UIFS HMVDPDPSUJDPJE FGGFDUT $BVUJPO TIPVME CF UBLFO JO QBUJFOUT 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 Most common adverse reactions (incidence â&#x2030;Ľ2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. DRUG INTERACTIONS Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects. USE IN SPECIFIC POPULATIONS )FQBUJD JNQBJSNFOU .POJUPS QBUJFOUT GPS TJHOT BOE PS TZNQUPNT of hypercorticism.

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.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

and all were able to return to a gluten diet, without symptoms. Of the 18 patients who had a biopsy, 17 had complete histologic recovery of the duodenum. “Ethically it is impossible to rechallenge these patients to prove causality,” Dr. Herman said. “However, anecdotally, challenge was redone in three patients prior to making this connection, all of whom developed severe diarrhea, nausea and vomiting.” These findings may be just the tip of the iceberg, she added, but evidence may be hard to obtain due to the long delay

between patients starting olmesartan, and the onset of symptoms. The Mayo researchers published their findings in Mayo Clinic Proceedingss (Rubio-Tapia A et al. 2012;87:732-738). Sheila E. Crowe, MD, professor of medicine, University of California, San Diego, in La Jolla, said she is interested in the study because it recalled a few of her patients with celiac disease whose conditions resisted treatment, or mysteriously worsened after first improving. “The first patient had ulcerative celiac disease. Her husband alerted us that ‘every

time she takes Benicar, she gets worse,’ ” Dr. Crowe said. Another patient’s refractory celiac disease improved after treatment with steroids and immunosuppressives, but when he regained weight and resumed taking his blood pressure medication—olmesartan—his condition deteriorated. When the patient switched to another antihypertensive medication, his symptoms improved. Dr. Crowe saw this pattern in a few patients, but she said it’s impossible to determine at this point what caused the

UCERIS™:

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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 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]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the endoscopic index [EI] score) after 8 weeks of treatment.1 *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.

symptoms to subside. “Maybe it was just a longer time on a gluten-free diet,” she said. “But I definitely believe this drug—and I don’t know how—is causing a problem.” She noted that although her patients are a somewhat different group from those described in the Mayo study, there may be some overlap. “I think more research needs to be done, but this certainly warrants reconsidering [using] that drug for anyone who has other choices for an antihypertensive [medication].” ■

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

Research Explores Relationship Between Gut Microbiome and Obesity BY GEORGE OCHOA Long understudied, the human microbiomeâ&#x20AC;&#x201D;the microbes, with their genomes, that dwell in and on the human bodyâ&#x20AC;&#x201D;is now under intense scrutiny. It is increasingly clear that â&#x20AC;&#x153;human indigenous microbial communities â&#x20AC;Ś play a larger 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 4ZNQUPNT 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)

role in human health and disease than previously recognizedâ&#x20AC;? (Relman DA. Nutr Rev v 2012;70:S2-S9). Last year, two studies provided evidence that antibiotics administered in early life can result in obesity, presumably by disturbing the gut microbiome. And in another study, researchers showed that disturbance of microbial communities in 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

obese individuals who undergo bariatric surgery can result in beneficial outcomes. â&#x20AC;&#x153;The important thing is that there are interesting theories and hypotheses about how bacterial flora â&#x20AC;Ś might contribute to the etiology of obesity,â&#x20AC;? said Philip Schauer, MD, director, Bariatric and Metabolic Institute, Cleveland Clinic, in Ohio. â&#x20AC;&#x153;This is an interesting 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).

who study the gut microbiome think that it plays a significant role in the obesity epidemic in concert with a variety of other risk factors, such as poor dietary habits or a sedentary lifestyle.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Ilseung Cho, MD, MS S and early and somewhat speculative area of research. It may challenge the notion that obesity is just due to not eating the right things and not exercising enough.â&#x20AC;? Likewise, Ilseung Cho, MD, MS, assistant professor of medicine, associate program director, Division of Gastroenterology, NYU School of Medicine, New York City, said, â&#x20AC;&#x153;Many investigators who study the gut microbiome think that it plays a significant role in the obesity epidemic in concert with a variety of other risk factors, such as poor dietary habits or a sedentary lifestyle. The microbiome plays a key role in a variety of host functions, including immune response and metabolism.â&#x20AC;?

Effect of Antibiotics Dr. Cho was the lead investigator on a study in mice that demonstrated that antibiotics altered the gut microbiome in such a way as to affect murine metabolism and cause increased adiposity (Cho I et al. Naturee 2012;488:621-626). Investigators administered subtherapeutic doses of penicillin, vancomycin, penicillin plus vancomycin, or chlortetracycline to young mice in their drinking water; a control group received no antibiotics. There were 10 mice per group. After an exposure period see Microbiome, page 23

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

â&#x20AC;&#x2DC;Many investigators

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Microbiome continued from page 20

of seven weeks, the mice did not differ significantly in weight gain, but all four antibiotic-exposed groups had significantly higher total fat mass (P<0.05) compared with controls, and most (with the exception of the vancomycin group) had higher percent body fat (P<0.05). The antibiotic exposure caused taxonomic changes in the microbiome, with the ratio of the phylum Firmicutes to the phylum Bacteroidetes elevated in the antibiotic-exposed mice. Additionally, there was evidence of metabolic changes. For example, glucosedependent insulinotropic polypeptide was elevated in the antibiotic-exposed mice, and glucose tolerance tests showed a trend toward hyperglycemia. “In our paper, we describe a model where, by exposing mice to low-dose antibiotics, we were able to alter their microbiome,” said Dr. Cho. “Altering their microbiome resulted in a metabolic change in the mice that led to increased adiposity. The paper demonstrates that we are able to affect host metabolism by altering the gut microbiome.” Around the same time that Dr. Cho and his colleagues published their results, a related paper about antibiotic exposure in infants was published in advance online (Trasande L et al. Int J Obess 2012 Aug 21 [Epub ahead of print]). “Knowledge of the importance of the microbiome in human development raises new issues about antibiotic use in children, as such exposures may disrupt the microbial ecology,” the authors wrote. In the longitudinal birth cohort study, investigators analyzed data from 11,532 children. Exposure to antibiotics during three early-life time periods (ages <6 months, 6-14 months, 15-23 months) was assessed by questionnaires that had been administered to the parents near the measured time interval. Body mass indices (BMIs) were examined at five time points (six weeks, 10 months, 20 months, 38 months and seven years). Exposure to antibiotics during the period before 6 months of age—and only during that period, of those studied—was consistently associated with increases in BMI from 10 to 38 months. At 38 months, children who had been exposed to antibiotics before 6 months had significantly higher standardized BMI scores (P=0.009) and were 22% more likely to be overweight than children who had not been exposed (P=0.029). The researchers controlled for known social and behavioral risk factors for obesity.

Effect of Bariatric Surgery Following the evidence that antibiotics can disrupt the microbiome comes evidence that bariatric surgery can do the same. In this case, the disruption may be a source of health benefits. “The things we do to the gut in gastric bypass could alter the gut flora in a positive way and could be a major factor in why patients lose weight,” said Dr. Schauer. In a study published in advance online (Graessler J et al. Pharmacogenomics J 2012 Oct 2 [Epub ahead of print]), researchers sought to ascertain exactly what happens to the human gut flora in patients who undergo Roux-en-Y gastric bypass (RYGB). “Postoperative modification of gut microbial composition could be directly related to the metabolic status of the patients,” wrote study authors Juergen Graessler, MD, PhD, Prof. Dr. med., head of the Division of

Pathological Biochemistry, and Stefan R. Bornstein, MD, PhD, Prof. Dr. med., director and chair of medicine, both from the Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University Dresden, Germany.

‘We are just beginning to appreciate how integral the gut microbiome is to human health and disease. I think that we will discover far-ranging effects of the microbiome on a wide variety of diseases, including cardiovascular disease, obesity, colorectal cancer and inflammatory bowel disease.’ —Ilseung Cho, MD, MS

The researchers aimed to characterize changes of gut microbial composition within an individual before and three months after RYGB. The six patients examined in this pilot study were morbidly obese (BMI >40 kg/m²) with type 2 diabetes. Through metagenomic sequencing, 1,061 microbial species were identified in the fecal DNA of these patients. Of these, 22 species (and 11 of 729 genera) were found to be significantly affected by RYGB and were possibly associated with postoperative metabolic changes. Firmicutes and Bacteroidetes were reduced, and the phylum Proteobacteria was increased. The authors observed that the shift to Proteobacteria might bring potential risk for bowel inflammation and colorectal carcinomas. Of the 22 affected species, 10 correlated with plasma total and low-density lipoprotein cholesterol levels, five with triglyceride level, and two with hemoglobin A1c level. These data suggest, the authors wrote, that metabolic changes may result not only from RYGB-induced malnutrition but modified gut microbiota composition. All six patients lost weight and showed an improved metabolic situation after three months, with alleviated type 2 diabetes and reduced inflammatory activity. “This is the first clinical demonstration of a profound and specific intraindividual modification of gut microbial composition by full metagenomic sequencing,” said Drs. Graessler and Bornstein. “A clear correlation exists between microbiome composition and gene function, with an improvement in metabolic and inflammatory parameters.” Dr. Schauer commented: “This is very early stuff, a small set of six patients, basically showing a correlation between surgery and changes in populations of

bacteria after surgery. A lot more work needs to be done to show that changes in bacteria are a cause of the improvement.” He also pointed out the lack of a control group in the study. Dr. Cho called the Graessler study “a good study that begins to demonstrate the associations between surgical interventions and the microbiome.” But, he pointed out a limitation of the study, saying that it, like most studies of its kind, only reported associations. “We will eventually need long-term studies to evaluate whether changes are durable,” Dr. Cho said. “And perhaps more importantly, how those changes affect the host. Associations may exist but may not have any clinical impact, so all that information remains to be explored.” Elaine Holmes, PhD, head of biomolecular medicine, Imperial College, London, who was not associated with the study, said the study “is important and adds to the body of literature that shows microbial alterations postsurgery. It is important to try to identify how the microbiome may contribute to the mechanisms of weight loss or weight gain. If we can mimic this effect pharmacologically without necessity for surgery, then this would be a less invasive and safer option and could be critical in controlling the increasing diabetes epidemic.” Dr. Holmes was a co-author of studies that reported alterations in the microbiome and metabolism of rats following RYGB (Li JV et al. Gutt 2011;60:1214-1223; Li JV et al. Front Microbioll 2011;2:183). About those studies, she commented: “Following gastric bypass surgery, there is an increase in Gammaproteobacteria and in Enterobacteria in particular. This was accompanied by alterations in metabolism including … energy metabolism, gut microbial metabolites such as cresols, and … amino acids and biogenic amines.” Dr. Holmes is currently engaged in a similar study in humans. “We have compared the results from surgery with nonsurgically achieved weight loss,” she said. “We have looked at samples up to one year postsurgery and still find a substantially altered microbiome and metabolism. The microbiome is unquestionably altered following bariatric surgery. This has been shown in both rodent models and in man.”

The Future Although research on the microbiome, obesity and bariatric surgery is still in its infancy, the general lines it will follow are beginning to be defined. “The microbiome does bear careful examination in the setting of bariatic surgery (a radical ecological disturbance), and will require time series analyses (with dense sampling before and after the procedure) in a significant number of subjects, in such a manner that a number of confounding variables are controlled,” said David A. Relman, MD, the Thomas C. and Joan M. Merigan Professor, Departments of Medicine and of Microbiology & Immunology, Stanford University, and chief, Infectious Diseases Section, VA Palo Alto Health Care System, Palo Alto, Calif. “The measurement of functional attributes will be very important.” “We are just beginning to appreciate how integral the gut microbiome is to human health and disease,” said Dr. Cho. “I think that we will discover far-ranging effects of the microbiome on a wide variety of diseases, including cardiovascular disease, obesity, colorectal cancer and inflammatory bowel disease.” ■

Gut Flora continued from page 1

compounds (VOCs)—or “breathprints”—in children with obesity or NAFLD differed from those of controls. Previous research in mice has shown that altering the intestinal microbiome can induce weight gain and also lead to the development of metabolic syndrome (Turnbaugh PJ et al. Nature 2006;444:1027-1031; Vijay-Kumar M et al. Science 2010:328;228-231). In the two current studies, lead investigator Naim Alkhouri, MD, director, Pediatric Preventive Cardiology and Metabolic Clinic, Department of Pediatric Gastroenterology, Cleveland Clinic, Ohio, and his colleagues used mass spectrometry to analyze exhaled breath from obese,

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

overweight or lean children and children with NAFLD. In the study of obese or overweight children, Dr. Alkhouri’s team compared the breath composition of 60 overweight or obese children (body mass index ≥85% for their age) with 55 lean children as a control group. The overweight or obese children had a mean age of 14 years, and the lean children had a mean age of 12 years. The obese or overweight children also were taller than the control group (mean height, 165 vs. 153 cm, respectively), and more of them were white (60% vs. 35%, respectively). The researchers controlled for these significant differences in their analyses. The researchers found that the concentrations of more than 50 VOCs tested differed significantly between obese and

‘W believe these findings will shed light ‘We ‘W on causes of childhood obesity, with potential implications for research and treatment. We will be conducting further research to see whether the altered gut flora is a cause or an effect of obesity.’ —Naim Alkhouri, MD D

overweight children and lean children. Using these findings, they built a predictive model composed of four of the

VOCs: isoprene, a cholesterol synthesis marker; 1-octene, a marker of oxidative stress; and ammonia and hydrogen

Weight Loss Reduces Systemic Inflammation in Obese Patients BY CHRISTINA FRANGOU When overweight or obese individuals lose weight with either a low-fat or low-carbohydrate diet, they experience a significant reduction in inflammation throughout their body as measured by three common markers for inflammation, according to recent research. “Our findings indicate that you can reduce systemic inflammation, and possibly lower your risk for heart disease. … The important factor is how much weight you lose, especially belly fat,” said study author Kerry Stewart, EdD, professor of medicine and director of clinical and research exercise physiology at the Johns Hopkins University School of Medicine, Baltimore. For the study, Dr. Stewart and his colleagues selected 60 individuals between the ages of 30 and 65 years who were overweight or obese, and had excessive fat around their waists. They were randomly assigned to adhere to a lowfat or low-carb diet for six months. Each group also participated in exercise training three times a week. The researchers assayed the participants’ blood for three markers of inflammation: C-reactive protein, interleukin 6 (IL-6), and tumor necrosis factor-alpha at the beginning and end of the study. They also measured body weight, body mass index (BMI), and total body and belly fat. At the start of the study, both groups had similar, elevated levels of inflammation markers. Participants on the low-carb diet lost more weight, on average, than those on the low-fat diet: 28 versus 18 pounds, respectively. The low-carb diet group also had a greater reduction in BMI (4.7 vs. 2.9 kg/m2, respectively), and a greater reduction in belly fat (14.3 vs. 8.4 lb., respectively). Both groups increased their level of aerobic fitness by about 20%.

“In both groups, there was a significant drop in the levels of all three measures of inflammation,” said Dr. Stewart, indicating that a diet higher in fat and protein does not interfere with the ability to lower the level of inflammation, as long as a person is losing weight. These findings, which were presented at the annual meeting of the American Heart Association last November, may have some relevance for overweight and obese patients who seek help for weight management from gastroenterologists. These patients often ask about low-carb versus low-fat diets. The study shows that weight loss improves metabolic syndrome parameters and reduces systemic inflammation.

‘Our findings indicate that you can reduce systemic inflammation, and possibly lower your risk for heart disease. … The important factor is how much weight you lose, especially belly fat.’ —Kerry Stewart, EdD

Asked if the findings might have any implications for patients with inflammatory bowel disease (IBD), Amar R. Deshpande, MD, assistant professor of medicine, University of Miami Miller School of Medicine, in Florida, was doubtful. In patients with IBD, inflammation tends to center around the gastrointestinal (GI) tract, and patients often struggle to put on weight, he said.

“In IBD, we focus on inflammation in the gut and not the markers they have examined here [in the study],” Dr. Deshpande said. Patients in the study experienced some systemic inflammation but not GI disease, which probably indicates that they absorb carbohydrates and fats normally, unlike people with IBD, particularly those with Crohn’s disease, who experience absorption problems in the GI tract. A more recent study published this year in Cell Metabolism (Deng T et al. 2013;17:411-422) showed that fat cells themselves can trigger an inflammatory response, possibly explaining the elevated levels of inflammatory markers observed in the overweight and obese individuals in Dr. Stewart’s study. In this study, researchers from The Methodist Hospital in Houston showed that high-calorie diets cause adipocytes to make major histocompatibility complex II, a group of proteins that is usually expressed in response to pathogens. When this happens, adipocytes trigger cells of the immune system to release proteins that are normally used to help fight off viruses and bacteria. In this case, however, there is no pathogen, and the fat cells merely trigger a cascade of events that leads to inflammation. “We did not know fat cells could instigate the inflammatory response,” said study author Willa Hsueh, MD, director of the Diabetes & Metabolism Institute at The Methodist Hospital System, in a press statement. “That’s because for a very long time we thought these cells did little else besides store and release energy.” Dr. Hsueh said that if she and her colleagues can identify the antigen(s) that is presented to cells in adipose tissue, they may be able to identify a new approach to target inflammation in obese patients. —Additional reporting by Cynthia J. Gordon, PhD

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

â&#x20AC;&#x2DC;T â&#x20AC;&#x2DC;These â&#x20AC;&#x2DC;T are intriguing but quite preliminary studies that may add to growing evidence that the intestinal microbiota play a role in determining an individualâ&#x20AC;&#x2122;s weight.â&#x20AC;&#x2122; â&#x20AC;&#x201D;L Law a re enc ce S. S Fri ried edma ed ma an,, MD

sulfide, both of which are byproducts of gut flora metabolism. Differences in the concentrations of these selected VOCs were distinct enough that the model accurately identified 92% of overweight or obese children (P<0.0001). â&#x20AC;&#x153;We believe these findings will shed light on causes of childhood obesity, with potential implications for research and treatment,â&#x20AC;? Dr. Alkhouri said. â&#x20AC;&#x153;We will be conducting further research to see whether the altered gut flora is a cause or an effect of obesity.â&#x20AC;? In a study of children with NAFLD, Dr. Alkhouriâ&#x20AC;&#x2122;s team analyzed exhaled breath from 37 obese or overweight children with NAFLD and 23 obese or overweight children without NAFLD.

They found distinctive â&#x20AC;&#x153;breathprintsâ&#x20AC;? among children with NAFLD, with the concentrations of more than 15 VOCs differing significantly from children without NAFLD. Again, the researchers developed a predictive model composed of a number of the VOCs: isoprene; acetone, a byproduct of glucose metabolism; trimethylamine, a byproduct of choline metabolism; acetaldehyde, a byproduct of ethanol metabolism; and pentane, a marker of oxidative stress. The researchers determined that this model correctly identified 90% of

children with NAFLD (P<0.0001). â&#x20AC;&#x153;Exhaled breath analysis is a promising noninvasive method to detect fatty liver in obese children. Future studies are needed to validate our findings,â&#x20AC;? the researchers concluded. â&#x20AC;&#x153;These are intriguing but quite preliminary studies that may add to growing evidence that the intestinal microbiota play a role in determining an individualâ&#x20AC;&#x2122;s weight,â&#x20AC;? said Lawrence S. Friedman, MD, chair, Department of Medicine at Newton-Wellesley Hospital, assistant chief of medicine,

Massachusetts General Hospital, and professor of medicine at Harvard Medical School and Tufts University School of Medicine, all in Boston. Dr. Friedman, who was not involved in the studies, added, â&#x20AC;&#x153;While it may be that the exhaled breath VOCs identified here are produced by the bowel flora as well as other metabolic processes intrinsic to the individual, both of these possibilities remain to be proven.â&#x20AC;? â&#x2013; Drs. Alkhouri and Friedman have no relevant conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Acid-Suppressing Drugs Are Overprescribed In Infants, Evidence Shows BY CAROLINE HELWICK NEW ORLEANS—Acid-suppressing drugs are overprescribed in infants and children, and this is a “risky business,” according to Eric Hassall, MBChB, of the Pediatric Specialty Clinic, California Pacific Medical Center, San Francisco. Dr. Hassall, professor of pediatrics at the University of British Columbia, Vancouver, delivered a plenary address on this topic at last year’s American Academy of Pediatrics National Conference and Exhibition. He acknowledged that proton pump inhibitors (PPIs) have huge benefits for symptomatic relief and healing of esophagitis when prescribed for children over the age of 1 year who have proven gastroesophageal reflux disease (GERD). However, these medications often are prescribed for infants who are spitting up or just irritable, and GERD is seldom responsible. “For the great majority of thriving, healthy infants, spitting up is ‘life,’ not a disease,” Dr. Hassall told meeting attendees in a talk that was one part gastroenterology and one part everyday pediatrics. Spitting up that occurs several times a day in healthy infants is normal, and diminishes over time. By definition, this is “physiologic reflux,” not reflux disease. Dr. Hassall said that the “flood of direct-to-consumer marketing since the mid-1990s” has created a demand for drugs to treat symptoms in infants that are, more often than not, not classic GERD. “Most infants [have] reflux, but it’s not acidd reflux. The advertiser-invented term acid refluxx suggests that an acid-suppressing drug is required,” Dr. Hassall said. “This creates demand by consumers for a drug that is very seldom indicated in infancy.” Common symptoms of unexplained crying and refusal to feed in infants more often are due to causes such as difficulty to “change state,” that is, to self-calm from a state of fussiness, whatever the initial cause. This is a function of immaturity of the nervous system, and it improves over time. GERD is less common than many other causes of infant irritability, such as food allergy, gassiness, difficulty sucking, swallowing air, constipation, or occasionally, infection or other underlying systemic disease. Dr. Hassall proved his point in a study of 162 infants with symptoms attributed to GERD. After failing one week of nonpharmacologic treatment, babies were randomized to four weeks of treatment with a PPI or placebo. In each group, 54% were considered to be “responders.” “The drug was no better than placebo, and there were more treatment-related adverse effects with the PPI,” Dr. Hassall said. “In otherwise normal infants with unexplained crying, there is no evidence to support acid suppression.”

Infant GERD After about 6 months of age, ongoing irritability, especially with feedings, is more likely to be related to GERD, Dr. Hassall said. Clinicians should appreciate that certain conditions do make GERD more likely: neurologic impairment (such as cerebral palsy); repaired esophageal atresia (or

other congenital esophageal condition); chronic lung disease (such as cystic fibrosis); hiatal hernia; obesity; and a family history of GERD, Barrett’s esophagus or adenocarcinoma. Outside of these potential causes, chronic GERD is a relatively uncommon occurrence. “It becomes a disorder when the reflux of gastric contents is the cause of troublesome symptoms or complications, and that’s when we define it as GERD. But the question is, ‘troublesome for whom?’ ” Of course, infants cannot give a reliable account of the nature of what is troublesome. “If it is just troublesome for the parents, is this really reflux disease, and should we treat it? Probably no, on both counts,” Dr. Hassall said.

Prescriptions Skyrocketing The use of acid-suppressing drugs in young children with presumed GERD increased sevenfold between 1999 and 2004, according to findings from a health claims database, which also demonstrated that prescriptions for a child-friendly liquid formation increased 16-fold (Barron JJ et al. J Pediatr Gastroenterol Nutr 2007;45:421-427). Overall, about 0.5% of roughly 1 million infants in the database received a PPI during their first year of life, half of them by the age of 4 months. In a more recent claims database, the diagnosis of GERD or “acid-related disorder” in infants and children quadrupled between 2000 and 2005 (Nelson SP et al. J Med Econ 2009;12:348-355). “It’s not as though the developed world is experiencing an epidemic of reflux disease in infants—rather, there are drugs marketed to treat symptoms that are not, in fact, reflux disease, and parents often desire a ‘quick fix,’ ” Dr. Hassall said.

Appropriate Use PPIs and histamine-2 receptor antagonists (H2RAs) can be used appropriately in infants and children. In children older than 1 year, with erosive and nonerosive esophagitis, PPIs are highly effective and well tolerated for healing (over three months) and maintenance (over two years). Once-daily dosing is usually adequate for healing severe cases, and higher doses on a per kilogram basis are required for children between the ages of 1 and 9 years. The duration of treatment with acid-suppressing drugs in children depends on the presence or absence of underlying predisposing conditions. In an Italian study, 46 children aged 3 to 13 years with erosive esophagitis were treated with omeprazole for three months and then randomized to receive omeprazole, ranitidine or placebo for six months (Boccia G et al. Am J Gastroenterol 2007;102:1291-1297). At one year, all patients were able to discontinue treatment. Because the study excluded GERD-predisposing conditions, it showed that in most patients without underlying conditions, GERD is not chronic and short-term treatment is appropriate, Dr. Hassall said. In contrast, a study by Dr. Hassall and his colleagues of 166 children who required continuous PPI use showed that multiple attempts to wean the children off treatment was unsuccessful. In this study, 80% of children had at least one GERD-predisposing

condition, and many had failed at least one fundoplication. PPIs were used in these children for up to 11 years (median, three years), and they responded extremely well to long-term PPI therapy (Hassall E et al. J Pediatr 2007;150:262-267). Dr. Hassall noted that no particular PPI has proven to be superior to another.

Adverse Effects “Gastric acid has physiologic/teleological purposes, so suppression of it, even for part of the day, may cause problems,” Dr. Hassall noted. A number of adverse effects of acid suppression with PPIs and H2RAs have been documented in children: • Acute gastroenteritis and community-acquired pneumonia in children aged 4 to 36 months receiving PPIs or H2RAs • Necrotizing enterocolitis in preterm infants receiving H2RAs • Candidemia in children in neonatal intensive care receiving H2RAs • Pneumonia in infants receiving PPIs • Pulmonary infections in children with asthma receiving PPIs “And anecdotally, in everyday pediatrics, we see lots of breast-fed infants who should not have coughs, pneumonia or gastroenteritis, but they get these on acid-suppressing drugs,” Dr. Hassall said. Other adverse effects, infectious and nutritional, have been seen in adults and could potentially occur in children as well. “Acid-suppressing drugs are invaluable in the management of several conditions in childhood, but there’s no free lunch; all drugs have potential adverse effects. So, the real risk is not in the prescribing of these drugs, it’s the overprescribing in patients who don’t warrant acid suppression.” Dr. Hassall takes a risk–benefit approach in his practice. “If the child has erosive esophagitis or demonstrable reflux disease, the benefits of acid suppression outweigh the risk,” he said. In the children who are not candidates for acid suppression, treatments include positioning, burping, avoidance of cigarette smoke, calming, temporizing, and very importantly, a trial of a change in diet. see Overprescribed, page 33

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

pH Monitoring continued from page 1

initial eight-week trial of PPI treatment could identify many patients who do not need treatment with PPIs, and could save thousands of dollars in unnecessary health care spending, researchers reported. â&#x20AC;&#x153;We spend a shocking amount of money on PPI use, and the numbers just keep increasing,â&#x20AC;? said lead investigator David Kleiman, MD, a research fellow in the Department of Surgery, Weill Cornell Medical College and NewYork-Presbyterian Hospital, New York City. â&#x20AC;&#x153;More and more papers are suggesting there is a lot of inappropriate use of PPIs for people who really do not need it, and our study supports this assertion,â&#x20AC;? Dr. Kleiman said.

in patients with unconfirmed GERD. According to Dr. Kleiman, 32% of patients had negative pH monitoring. His team estimated that conducting a pH monitoring study immediately after an eight-week trial of PPIs could have saved up to $7,285 per patient over a 10-year period, assuming that pH monitoring is 100% sensitive. Dr. Kleiman added that even with a 35% sensitivity rate, performing a pH monitoring study after an eight-week trial would still be a cost-effective strategy. Lawrence S. Friedman, MD, chair of

the Department of Medicine at NewtonWellesley Hospital, assistant chief of medicine, Massachusetts General Hospital, and professor of medicine at Harvard Medical School and Tufts University School of Medicine, all in Boston, said: â&#x20AC;&#x153;It must be considered that even esophageal pH monitoring is neither entirely sensitive nor specific for GERD. More importantly, patients in the study who continued PPI therapy for long periods may have had symptomatic improvement, even in the absence of an abnormal esophageal pH result, and the prolonged

use of a PPI may have been appropriate from the point of view of the patient and the physician.â&#x20AC;? However, Dr. Friedman, who was not involved in the study, said that â&#x20AC;&#x153;any opportunity to reduce the dose of a PPI or eliminate the drug altogether should be encouraged if continued use of the PPI is not clinically beneficial. A secondary benefit, especially as we shift to value-based care, is a reduction in costs,â&#x20AC;? he said. â&#x2013; Drs. Kleiman and Friedman have no relevant conflicts of interest.

THE ULTIMATE ENDOSCOPY R ETREAT

â&#x20AC;&#x2DC;We spend a shocking amount of money on PPI use, and the numbers just keep increasing.â&#x20AC;&#x2122;

RL AU Y B GU I R D ST D 6, E A 20 D L 13 I N E

â&#x20AC;&#x201D;David Kleiman, MD

- */ ,Ă&#x160;Ă&#x201C;Ă¤Â&#x2021;Ă&#x201C;Ă&#x201C;]Ă&#x160;Ă&#x201C;Ă¤ÂŁĂ&#x17D;Ă&#x160;Ă&#x160;Ă&#x160;Ă&#x160;Ă&#x160;Ă&#x160;Ă&#x160;Ă&#x160;Ă&#x160; 7Ă&#x160; ,, "//Ă&#x160; -Ă&#x160;6 -Ă&#x160;, -",/Ă&#x160; Ă&#x160;-* Ă&#x160;UĂ&#x160; -Ă&#x160;6 -]Ă&#x160; 6 Professional guidelines recommend pH monitoring if a diagnosis of GERD is still in question following upper endoscopy and an eight-week trial of PPIs, Dr. Kleiman said. However, he noted that many physicians do not adhere to this protocol. To document the costâ&#x20AC;&#x201C;benefit of following this approach, Dr. Kleiman and his colleagues from other research centers analyzed retrospective data of pH monitoring in 100 patients with suspected but unconfirmed GERD, most of whom had refractory symptoms despite long-term PPI use. Eighty-three of the patients had esophageal symptoms of GERD, and 17 had extraesophageal symptoms. Patients with esophageal or extraesophageal symptoms of GERD were referred for pH monitoring after a median of 208 and 52 weeks of PPI therapy, respectively. Cumulatively, patients had undergone 21,411 weeks of PPI therapy beyond the eight-week trial, after which pH monitoring is recommended

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DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

GI Complications on the Rise From Ingestion Of High-Powered Magnetic Balls by Children Researchers Report High Rate of Endoscopic, Surgical Interventions BY CAROLINE HELWICK ORLANDO— —A dramatic increase has been observed in gastrointestinal emergencies in children, attributed to the ingestion of tiny, high-powered magnetic balls that

are sold as adult desk toys, investigators reported at the 2013 Digestive Disease Week meeting. “We seemed to be seeing more and more of these cases, some of which were very serious, even life-threatening,” said study author Adam Noel, MD, associate

professor of pediatrics at Louisiana State University Health Sciences Center and a pediatric gastroenterologist at Children’s Hospital in New Orleans, who first reported the findings at a press briefing at last year’s American Academy of Pediatrics National Conference and Exhibition.

‘We seemed to be seeing more and more of these cases, some of which were very serious, even lifethreatening.’ —Adam Noel, MD D

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Volume 64, Number 1 • January 2013

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“Our research not only confirms our concern, but also shows that early intervention is particularly important with these magnet ingestions.” The 2-mm neodymium magnets—which also are found in computer hard drives, automobiles and power tools—are 10 to 20 times stronger than typical refrigerator magnets and can attract through half an inch of muscle, skin and bone. The attachment of two or more balls can cause perforation of gastrointestinal structures within 12 hours of ingestion, researchers said. “I don’t think people understand the implications of this simple little toy and the danger it causes for children,” said senior author of the study, Mark Gilger, MD, professor of pediatrics at Baylor College of Medicine and a pediatric gastroenterologist at Texas Children’s Hospital, both in Houston. Based on an observed increase in cases of magnet ingestion reported in the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) bulletin board in the spring of 2012, Drs. Noel and Gilger performed a survey of NASPGHAN members to study the changes in frequency and complications associated with magnet ingestion in children. The survey was focused on providing information on medical and surgical interventions required in patients who ingested magnets during the period from 2008 to the fall of 2012, the time in which neodymium magnet ball sets were marketed in the United States. Survey respondents reported 123 cases between 2008 and 2012, with 102 cases occurring between 2011 and 2012. Among the key findings: • 98% of patients underwent at least one x-ray, with nearly 70% requiring serial x-rays. • Nearly 80% of patients required endoscopy, surgery or both.

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

‘When you realize that almost 10% of these children require long-term care because they ingested a toy, that is just not acceptable.’ —Adam Noel, MD

• Of the patients who required endoscopy, surgery or both, about 25% of patients underwent some type of surgery, including laparotomy, laparoscopy and thoracotomy. • Among surgical cases for magnet removal, 43% of patients required an additional surgical procedure, including fistula repair (60%) and bowel resection (15%). • 21% of cases could be managed by observation alone, or by observation and pumping of the stomach or lavage. The number of balls ingested did not correlate with the type of intervention required: e.g., 3% of surgery patients ingested more than 10 balls compared with 20% of patients who underwent endoscopy alone. In general, patients managed by endoscopy had less morbidity than those needing endoscopy plus surgery or surgery alone. And among patients who underwent surgery, outcomes were good for about 90% of patients; however 9% of patients needed long-term care—such as bowel rehabilitation—due to complications, Dr. Noel said. “When you realize that almost 10% of these children require long-term care because they ingested a toy, that is just not acceptable,” he said. Notably, the spike in magnet ingestion occurred during the past two years, after the products began including warning labels to prevent contact with children. In 2012, the warnings were further developed to advise that children under the age of 14 years should not play with the magnets. At last year’s American Academy of Pediatrics meeting, Dr. Noel noted that “despite improved warnings, the prevalence of high-powered magnet ingestions is increasing, which tells us that warnings are ineffective at prevention. The most effective way to prevent ingestion is to ban their sale.” In April, in response to increasing reports of the hazards associated with magnet ingestion, as well as work by NASPGHAN and the American Academy of Pediatrics, the U.S. Consumer Product Safety Commission and several

rretailers announced the voluntary recall of high-powered magnet sets. Although children between the ages of 13 months and 6 years are at the highest risk for magnet ingestion, the researchers noted a changing patient demographic, with an increase in events among teenagers who use the magnets for body jewelry and fake piercings. In a soon-to-be published paper in the Journal of Pediatric Gastroenterology and Nutrition, Drs. Gilger and Noel report on trends in emergency department

(ED) visits involving magnet ingestion by children younger than 18 years between 2002 and 2011 (Abbas MI et al. 2013 Apr 10 [Epub ahead of print]). They estimated that 16,386 children (<18 years) presented to EDs in the United States between 2002 and 2011 with possible magnet ingestion. The majority of patients were younger than 5 years (54.7%); however, from 2009 to 2011, there was an increase in multiplemagnet ingestion by older children (mean average age, 7.1 years). “The findings send a strong message to clinicians and parents,” Dr. Noel concluded.

“Although they look harmless on an x-ray, these magnets are powerful enough to cause serious damage to the digestive track in a short amount of time.” ■ —Additional reporting by Cynthia J. Gordon, PhD Dr. Gilger has received grant/research support from QOL Inc. and Redhill Biopharma, and has served as a speaker for AstraZeneca and Abbott Laboratories. Dr. Noel and Swanson reported no conflicts of interest.

Think of Enterography as a GPS for Crohn’s disease.

Image shows not only thickening of the bowel wall, but also the increased attenuation of the mucosa compatible with active Crohn’s disease.*

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery. Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

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

Burnout continued from page 1

Gastroenterologists were among 10 medical specialties that experienced the lowest rates of burnout; 37% of gastroenterologists reported being burned out, just above dermatologists, at 36% (Figure). Psychiatrists (33%) and pathologists (32%) reported the lowest rates of burnout. The highest rates of burnout were reported by physicians in emergency medicine (52%) and critical care (50%). Among all physicians, 39.8% responded that they were burned out and 60.2% said that they were not. Medscape defined burnout as feeling any or all of the following symptoms: cynicism, loss of enthusiasm for work or low sense of personal accomplishment. These findings are similar with a study published by Shanafelt et al in 2012 that examined burnout among U.S. physicians using the same criteria ((Arch Intern Med 2012;172:1377-1385). In this study, researchers found that 45.8% of physicians experienced at least one symptom of burnout, with the highest rates among physicians “at the front line of care access” (e.g., family medicine, general internal medicine and emergency medicine). The findings of both studies support

10%

20%

30% 30%

40%

50%

60%

Figure. Fewer gastroenterologists reported burnout than physicians in other specialties. Reprinted with permission from Medscape (http://www.medscape.com), 2013. http://www.medscape.com/features/slideshow/lifestyle/2013/public

those of a 2011 study that looked at the degree of stress and burnout in 410 endoscopists (Keswani RN et al. Am J Gastroenteroll 2011;106:1734-1740). Researchers found that emotional exhaustion, reported in 30% to 63% of

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respondents, was the major contributor to burnout. Complexity of procedures and physician age were also main reasons for burnout, with interventional endoscopists and younger attending physicians reporting higher levels of burnout.

‘The major points of our 2011 study and the recent Medscape survey are that levels of stress and burnout are significant in gastroenterologists, but I believe that the survey likely underestimates burnout in gastroenterologists.’ —Rajesh N. Keswani, MD

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“The major points of our 2011 study and the recent Medscape survey are that levels of stress and burnout are significant in gastroenterologists, but I believe that the survey likely underestimates burnout in gastroenterologists,” said Rajesh N. Keswani, MD, assistant professor in medicine-gastroenterology and hepatology at Northwestern University Feinberg School of Medicine, Chicago. “We found that gastroenterologists often thought about how they could have prevented negative procedure outcomes, had difficulty sleeping at night due to thinking about procedures from the day, and had difficulty separating work and personal life.” However, Lawrence Cohen, MD, clinical professor of medicine at Mount Sinai School of Medicine, in New York City, believes the Medscape survey overrated the number of gastroenterologists who suffer from burnout.

“I define physician burnout as physical and emotional exhaustion, combined with diminished sense of personal satisfaction and accomplishment,” Dr. Cohen said. “Based upon my anecdotal experience, I would say that fewer than 10% of gastroenterologists [not 37%] suffer from true burnout. While I do believe that the vast majority of gastroenterologists are working harder than previously, they remain fully engaged in their professional activities, are satisfied emotionally and continue to be rewarded intellectually.”

Medscape Survey Says … The Medscape survey comprised responses from 24,216 U.S. physicians in 25 specialties, 2% of whom were gastroenterologists. Of the gastroenterologists who responded, 83% were men; more than 60% were 45 years and older; and 94% were board certified. Severity of burnout—with a measure of 1 being “does not interfere with my life” and 7 being “so severe that I am thinking of leaving medicine altogether”—was highest among OB/GYNs and pathologists, at 4.1 and 4, respectively. General surgery, with a mean score of 3.9, was one of six specialties tied for third place. Gastroenterologists reported slightly less severe burnout, with a mean score of 3.6. “Surgeons are at particular risk for burnout as we are taught early on that exhaustion is perceived as a status symbol and to base our self-worth on being productive,” said Henry Kuerer, MD, PhD, professor of surgery, University of Texas MD Anderson Cancer Center, Houston. “I worry that the burnout rate may be higher, as the survey might not capture even more harried physicians or those who have left their profession.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Too many bureaucratic tasks and spending too many hours at work, as well as the impact of the Affordable Care Act, topped the list of main stressors leading to burnout among gastroenterologists. The least important stressors were problems with employers, compassion fatigue and difficult colleagues or staff. “The introduction of EMR [electronic medical records] has contributed to the problem of physician burnout to the extent that some of my colleagues have quit because of it,” said Robert J. Fitzgibbons, MD, Harry E. Stuckenhoff Professor of Surgery, Creighton University School of Medicine, Omaha, Neb. “EMR has increased the amount of paperwork tremendously, and what’s particularly disturbing, EMR is a poor way of keeping records.” Dr. Fitzgibbons said that the electronic forms often provide choices that do not adequately reflect patient information and each form takes about 30 minutes to fill out. After seeing 25 patients a day, Dr. Fitzgibbons has hours of paperwork to complete at home. “I spend a lot of time inputting patient information, yet I get a worse record, whereas in the past it took five minutes to dictate a summary of the patient visit.” Although long hours likely contribute to career dissatisfaction, John Maa, MD, noted that another reason for burnout among some surgeons may be a perceived lack of rewards, including financial and societal prestige. “After long years of arduous training, some older general surgeons in practice have become concerned about the sustainability of the current residency training paradigm, the future practice of general surgery, and feel that the years of investment they made are not returning the rewards they had anticipated,” said Dr. Maa, who is assistant professor, Division of General Surgery, University of California, San Francisco, and director of the UCSF Surgical Hospitalist Program. Dhruv Khullar, a medical student and class president at Yale University School of Medicine and a student at Harvard University’s Kennedy School, agreed that many factors contribute to burnout, namely large workloads, long hours, loss of autonomy and an increasing amount of administrative work. But he believes these are symptoms of a greater problem. “I think what’s at the heart of the problem is that these challenges make it difficult for trainees and physicians to continue to focus on the reasons they got into the profession,” he said. “In the midst of the day-to-day grind, it can be easy to lose one’s enthusiasm and drive for providing the highest-quality, compassionate care.” The Medscape survey also revealed that the rate of burnout is lowest among the youngest and oldest gastroenterologists

‘I worry that the burnout rate may be higher, as the survey might not capture even more harried physicians or those who have left their profession.’ —Henry Kuerer, MD, PhD

and peaks in midlife, with 35% of those burned-out between the ages of 36 and 45 years, falling to 5% among those older than 65 years and probably related to retirement or reduced work hours. Consistent with most specialties, female

gastroenterologists appeared to be slightly more burned out than their male counterparts (37% vs. 32%, respectively). Medscape proposed that women may experience greater burnout because of more conflicts between work and home life.

In terms of physical health, the survey found that burned-out physicians tended to weigh more and exercised less than their less stressed counterparts: 46% of burned-out gastroenterologists reported being overweight or obese versus 36% of their peers not experiencing burnout, and 42% claimed to exercise two times per week versus 69% of their peers. Drinking and smoking habits as well as religiousness did not appear to be associated with level of burnout among gastroenterologists. see Burnout, page 32

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Burnout continued from page 31

Burnout Fallout Although the impact of burnout is not well understood, it may be serious, in some instances resulting in medical errors and an exodus of physicians from medicine. “We do not know the full impact of stress and burnout in gastroenterologists, but prior studies have shown that higher levels of burnout tend to result in early retirement; thus, those physicians with

the most experience may prematurely leave medicine,” said Dr. Keswani. “Even more concerning, it has been suggested in the surgical literature that higher levels of burnout were associated with medical errors,” although it is unclear if burnout was the cause of increased errors. Supporting this idea, a survey of more than 7,900 members of the American College of Surgeons showed that the number of hours worked and nights on call per week have a strong impact on surgeons’ level of burnout, depression and career satisfaction (Balch CM et al.

J Am Coll Surgg 2010;211:609-619). For instance, surgeons who worked more than 80 hours per week reported more medical errors than those who worked fewer than 60 hours per week (10.7% vs. 6.9%, respectively; P<0.001), and these overworked surgeons were twice as likely to attribute the error to burnout (20.1% vs. 8.9%%, respectively; P=0.001). P “There is an unhealthy scarcity mentality that is becoming pervasive in health care systems: not enough patients, money, time, reimbursements, etc.,” Dr. Kuerer said. “Hospitals and their physicians

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are afraid that they will not be able to compete. To some extent this promotes innovation, but also has the risk of demoralizing and demotivating not only physicians but all employees in the system.”

Combating Burnout Dr. Maa said surveys like this one can be helpful if they “provide constructive feedback on how to make improvements” and “raise awareness with patients, the federal government and other quality improvement organizations of the demands being placed upon physicians across specialties.” The next step to understanding the problem of physician burnout is developing ways to combat it. Many studies have demonstrated that increased levels of burnout in physicians may be reversible with a variety of focused interventions. “The studied interventions generally consist of counseling and mindfulnessbased stress reduction exercises,” Dr. Keswani said. “Perhaps more intriguing is the potential use of senior physicians as mentors to prevent burnout in junior colleagues.” Dr. Cohen noted that the best way to avoid burnout is to “diversify professionally.” “[This] can be done by volunteering to teach medical students, residents or gastroenterology fellows; learning new professional skills to expand your curcur rent practice abilities; and deveeloping new initiatives, such as clinical research [or] pathology laboratory [skills]. At the same time, it’s important to maintaain personal relationships with family and friends, and to develop interests outside of medicine that provide intellectual and em motional gratification.”

‘Prior studies have shown that higher levels of burnout tend to result in early retirement; thus, those physicians with the most experience may prematurely leave medicine.’ —Rajesh N. Keswani, MD Mr. Khullar believes that an important component of the solution is to create an environment that focuses on the importance of patient care and allows doctors to process and feel energized by these encounters. “For instance, at my medical school, there was an option to attend weekly sessions at which students discussed what they were enjoying or struggling with in their training. Similarly, a friend recently told me of an attending that always made sure his team took time to thoroughly discuss a patient’s death or other difficult

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Overprescribed continued from page 26

“Only as a last-ditch effort do you prescribe an acid-suppressing drug,” Dr. Hassall said, adding that his first-line option is a self-limited trial of an H2RA.

Rogue Prescribers Christopher Jolley, MD, professor and chief of pediatric gastroenterology, hepatology and nutrition at the University of Florida College of Medicine in Gainesville, agreed that the “dramatic increase in PPI usage is concerning” and said that Dr. Hassall’s comments regarding the risks associated with PPI usage in a population not at risk for significant GERD are “right on target.” Dr. Jolley concurred that “not all that cries or spits up is acid reflux disease. Most of it probably isn’t.” Regarding the overprescribing of PPIs, he said, “Although the marketing of these agents has played a role, I would bet that the change in prescribing practice represents greater perceived familiarity with PPIs among primary care physicians and perhaps more importantly,

their numerous extenders. I don’t think the majority of PPI prescription increase represents gastroenterologists’ practice. In addition to physicians, parents should be educated about treating infants for suspected GERD. A recent study published in the May issue of Pediatrics showed that parents who were told their infants had a diagnosis of GERD were interested in medication, even when they were told that the medications are likely ineffective (Scherer LD et al. 2013;13:839-845). In this study, researchers surveyed parents in a general pediatric

clinic who were given a hypothetical clinical scenario describing an infant who “cries and spits up excessively but is otherwise healthy.” Parents were randomized to receive a scenario in which a doctor gave a diagnosis of GERD or did not provide a disease label. The researchers found that parents who received a GERD diagnosis for their infants were interested in medication, regardless of potential efficacy. Dr. Jolley observed that oftentimes infants coming to see a gastroenterologist are already on PPI therapy. “By the time the gastroenterologist

For further reading, see Hassall E. Over-prescription of acidsuppressing medications in infants: how it came about, why it’s wrong, and what to do about it. J Pediatr 2012;160:193-198.

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Refresh, Recharge, and Learn experiences on the wards. Things like that go a long way [toward] preventing burnout and maintaining professional satisfaction.” Dr. Maa agreed that acknowledging burnout in colleagues and oneself may help reduce it, but he also proposed taking actions that extend beyond the hospital. “I believe the crucial next steps are for surgeons to vigorously engage in the health care reform debate, and pave new career paths and goals, particularly in the fields of government and public policy,” he said. Although the problem of burnout is important, what keeps Dr. Fitzgibbons motivated is simple: loving his job. “One can always complain, but in the end being a surgeon is a wonderful job. I would never want to have another career.” ■

sees these infants, they’re often drowning in PPIs, and failing,” he said. “I think we need to look first at who’s prescribing these drugs, and reeducate accordingly. Certainly, gastroenterologists need to be reminded, but to overlook a larger PPIprescribing base at the primary care level misses the target.” ■

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FDA Approves Obesity Drug Qsymia For Distribution Through Certified Retail Pharmacies In April, the FDA approved an amendment and modification to the Risk Evaluation and Mitigation Strategy (REMS) for Qsymia (phentermine and topiramate extended-release) capsules CIV, manufactured by Vivus. The amendment allows Qsymia to be dispensed through certified retail pharmacies, in addition to the existing network of mail order pharmacies. “With FDA approval of the REMS modification, we begin the process of increasing the availability of Qsymia, simplifying prescribing and dispensing, and resolving the challenges associated with the mail order–only system,” said Peter Tam, president of Vivus. “Our goal … is to ensure availability of Qsymia in thousands of certified retail pharmacies nationwide. The REMS modification is a key accomplishment in removing a major barrier that has hindered the initial acceptance of Qsymia into everyday medical practice. We believe that retail access, along with ongoing improvements in reimbursement, will help to accelerate Qsymia awareness, trial and usage.” The components of the original Qsymia REMS will continue to be available as part of the modified Qsymia REMS program, including a medication guide, patient brochure, voluntary health provider training and other educational tools.

Photo courtesy of Vivus, Inc.

According to a press release issued by Vivus in April, Qsymia will be available at certified retail pharmacies within 90 days. Health care providers and patients should continue to use the current, certified mail order network until further notice. Qsymia is approved in the United States and is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of at least 30 kg/m2 (obese), or 27 kg/m2 or greater (overweight) with the presence of at least one weight-related medical comorbidity, such as high blood pressure, type 2 diabetes or high cholesterol. Common side effects associated with Qsymia include dizziness, insomnia, constipation and dry mouth. Contraindications include pregnancy, glaucoma, hyperthyroidism and use of monoamine oxidase inhibitors. —Based on a press release from Vivus, Inc.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

FDA Approves Aciphex Sprinkle For Use in Children Ages 1 to 11 In March, Eisai Inc., announced the FDA approval of Aciphex Sprinkle (rabeprazole sodium), delayed-release capsules, 5 and 10 mg, for the treatment of gastroesophageal reflux disease (GERD) in children aged between 1 and 11 years, for up to 12 weeks. The granule contents can be sprinkled on a small amount of soft food or into a small volume of liquid. The approval was based on a multicenter, double-blind, parallel group study of 127 pediatric patients, between 1 and 11 years old, who were endoscopically diagnosed with GERD. The trial consisted of a 12-week treatment period and a 24-week extension period of two dose levels of Aciphex. Overall, 81% of the study participants achieved healing of lesions during the 12-week period and the response was sustained in 90% during the ensuing 24 weeks. The absence of a placebo group did not allow the evaluation of continuing efficacy through 36 weeks. The most commonly Aciphex Sprinkle, delayed-release reported adverse effects capsule, 5 mg (AEs) occurring in more than Photo courtesy of Eisai Inc. 5% of subjects during the 12-week treatment period included cough (14%), abdominal pain (12%), diarrhea (11%), pyrexia (10%) and headache (9%). In the 24-week extension period, the most commonly reported AEs (≥5% of patients) included upper respiratory tract infection (13%), vomiting (11%), abdominal pain (8%) and diarrhea (6%). Aciphex is a proton pump inhibitor. In addition to Aciphex Sprinkle, Aciphex is available as a 20 mg, delayed-release, enteric-coated tablet for the treatment of GERD in adults and adolescents aged 12 years and older. For more information, visit www.aciphex.com. —Based on a press release from Eisai Inc.

FDA Limits Duration and Usage of Tolvaptan Due to Possible Liver Injury The FDA has determined that tolvaptan (Samsca, Otsuka America Pharmaceutical, Inc.) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver transplant or death. The FDA has worked with the manufacturer to revise the tolvaptan drug label to include new the limitations. Tolvaptan is a selective vasopressin V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure and syndrome of inappropriate antidiuretic hormone. An increased risk for liver injury was

observed in recent large clinical trials that were evaluating tolvaptan for a new use in patients with autosomal dominant polycystic kidney disease. The FDA recommended that tolvaptan should be stopped if a patient Photo courtesy of Otsuka develops signs of liver disease. Treatment duration should be limited to 30 days or less, and use should be avoided in patients with underlying

liver disease, including cirrhosis. Physicians should inform patients that the drug may cause liver problems, including life-threatening liver failure. Health care professionals and patients can report adverse events or side effects related to the use of tolvaptan to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at www. fda.gov/MedWatch/report.htm. —Based on a press release from the FDA

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Acing the GI Board Exam: The Ultimate Crunch-Time Resource

Brennan Spiegel August 11, 2011 Many board review manuals provide lists and bullet points lacking sufficient background and context. This book presents time-tested and highyield information in a rational, useful and contextually appealing format.

Biologics in Inflammatory Bowel Disease

Scott Plevy March 1, 2014 The Oxford American Pocket Notes: Biologics in Inflammatory Bowel Disease e is a practical guide to the safe administration of biologic agents to treat inflammatory gastrointestinal illnesses. This ultra-concise and practical volume focuses on tumor necrosis factor (TNF) blocking therr apy, an important new class of biologic therapy indicated for the treatment of several rheumatic and other autoimmune disorders, including Crohn’s disease and ulcerative colitis.

Common Liver Diseases and Transplantation: An Algorithmic Approach to Work Up and Management

Robert S. Brown Jr. December 15, 2012 This book provides a review of liver diseases and transplantation that is comprehensive enough to provide an intellectual basis for the data, yet simple enough to be read and assimilate into clinical practice rapidly.

Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

John Dibaise April 20, 2012 This is a unique question and single-answer review for gastroenterology in-service and board exams. The book features 3,500 questions with only the correct answer provided, reinforcing the answer students need to remember on exam day. Emphasis is placed on distilling key facts and c ca pearls clinical pea s essential esse t a for o exam e a success. success

Gastrointestinal Endoscopy in the Cancer Patient

John C. Deutsch; Matthew R. Banks May 6, 2013 This book is a full-color, highly clinical multimedia atlas focusing on the role diagnostic and therapeutic endoscopy plays in the management of patients with cancer. Conveniently split into sections for each part of the GI tract, each section will follow a consistent structure. With 400 highquality images and 21 high-definition videos showing endoscopy from the experts, this book is the perfect consultation and learning tool for all gastroenterologists, endoscopists, GI surgeons and oncologists.

Morson and Dawson’s Gastrointestinal Pathology

Neil A. Shepherd; Bryan F. Warren; Geraint T. Williams; Joel K. Greenson; Gregory Y. Lauwers; Marco R. Novelli February 15, 2013 Emphasizing the important role the gastrointestinal pathologist plays in patient management, this book is a comprehensive resource for both training and practice. This textbook reflects current practice, where the abundance of surgical specimens and the revolution in endoscopy has made virtually the entire gastrointestinal tract accessible to biopsy.

Non-Alcoholic Fatty Liver Disease: A Practical Guide

Geoffrey C. Farrell; Arthur J. McCullough; Christopher P. Day April 15, 2013 The sharp rise in cases of non-alcoholic fatty liver disease (NAFLD) is fast becoming one of the major concerns for hepatologists worldwide. This comprehensive clinical guide explains how to diagnose NAFLD and manage patients according to the best standards of care.

Practical Manual of Gastroesophageal Reflux Disease

Marcelo F. Vela; Joel E. Richter; John E. Pandolfino February 15, 2013 Highly practical, expertly written and packed with useful text tools like case histories, pitfall boxes and management algorithms, this convenient and user-friendly manual provides a complete clinical guide to gastroesophageal reflux disease, one of the most common conditions that g gastroenterologists g face every y day. y GEN0613

F D A U P D AT E & P R O D U C T N E W S

FDA Grants Additional 510(k) Clearance for NvisionVLE Imaging System

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

FDA Asks for More Data on Dynavax’s Adult Hepatitis B Vaccine

Medical device manufacturer NinePoint Medical Inc., has received addiThe FDA has denied approval for events. According to a statement tional 510(k) clearance from the FDA for its NvisionVLE Imaging System, Heplisav, an investigational vaccine issued by Dynavax, the FDA also expanding the system’s indication to include imaging of esophageal tissue for hepatitis B virus (HBV) infection requested additional data on its microstructure. developed by Dynavax Technolo- process validation program and “The NvisionVLE Imaging System is the first and only volumetric, optical gies Corporation. Heplisav, a Phase the manufacturing controls and coherence tomography device cleared by the FDA for endoscopic imagIII candidate, combines hepatitis facilities related to assurance of the ing, and now imaging of esophageal tissue microstructure,” said Charles B surface antigen with a propri- quality of the drug. Carignan, MD, president and CEO of NinePoint Medical. etary toll-like receptor 9 agonist to In November 2012, the FDA’s “Expanded FDA 510(k) clearance for imaging of the esophagus repreenhance the immune response. Vaccines and Related Biologisents an important milestone as we progress toward commercializing the In February, the FDA issued cal Products Advisory Committee NvisionVLE Imaging System this year. We believe [the system] will allow a complete response letter in found that the data on Heplisav physicians to see more esophageal tissue for biopsy and treatment proresponse to Dynavax’s biologic adequately demonstrated immunocedures, providing them with valuable imaging information.” license application stating that the genicity but that there were insufIn January 2012, the company received FDA 510(k) clearance for Nviindication for Heplisav in adults ficient data to support its safety. sionVLE for use as an imaging tool in the evaluation of human tissue between the ages of 18 and 70 Dynavax plans to meet with the microstructure by providing two-dimensional, cross-sectional and realyears could not be approved with- FDA for discussions regarding a time depth visualization. out further evaluation of safety more restricted use for Heplisav. The NvisionVLE Imaging System enables physicians and pathologists to for this group. The agency also —Based on a press release from evaluate the tissue microstructure during a standard endoscopy procedure expressed concern that novel adjuDynavax Technologies and provides real-time, high-resolution, volumetric images of organs and vants may cause rare autoimmune tissues up to 3 mm deep at a resolution of better than 10 microns. The system uses a high-resolution display and proprietary software to provide an image that can be reviewed by a physician to identify areas of suspicion such as inflammatory, metaplastic or dysplastic changes, or possible cancers. On April 30, Mauna Kea Techthe missing information needed The safety and effectiveness of the nologies announced the FDA to separate the high-risk versus NvisionVLE for diagnostic analysis 510(k) clearance of the AQ-Flex low-risk cysts and impact patient (i.e., differentiating normal from spe19 miniprobe. The product is management,” Dr. Chang said. cific abnormalities) in any tissue microdesigned to provide real-time The FDA clearance of the AQstructure or specific disease has not optical biopsies during endoFlex 19 miniprobe marks the been evaluated. scopic ultrasound-guided fine sixth regulatory clearance in the —Based on a press release from NinePoint M Medical Inc. needle aspiration procedures in United States for Mauna Kea, the digestive tract. whose flagship product, Cellvizio, The AQ-Flex 19 miniprobe is a probe-based, confocal, laser is the first-ever needle-based endomicroscopy system that confocal laser endomicroscopy provides physicians with highproduct, extending optical biopresolution cellular views of tissue sies into previously unreachable inside the body. The AQ-Flex 19 areas. Measuring just 0.8 mm miniprobe is compatible with all in diameter, the AQ-Flex miniCellvizio 100 series systems. probe will be made immediately According to Mauna Kea, a available in the United States, growing number of pancreatic according to the manufacturer’s cysts are being diagnosed in The AQ-Flex 19 miniprobe provides real-time optical press release. the United States every year biopsies during EUS-guided “With needle-based optical as a result of the estimated 70 FNA procedures. biopsies, we now have access million scans being performed. Photo courtesy of Mauna Kea to absolutely unique, real-time Data from a large retrospective Technologies dynamic views of the cellular and analysis showed that pancreatic vascular structures of previously unreachable areas cysts were present in 2.4% of asymptomatic patients such as pancreatic cysts,” said Kenneth J. Chang, MD, who underwent computed tomographic scans of the professor and chief of the Division of Gastroenterology abdomen for non-pancreatic issues (Laffan TA et al. and executive director of the H.H. Chao Comprehen- AJR Am J Roentgenoll 2008;191:802-807). However, The NvisionVLE Imaging System sive Digestive Disease Center at the University of Cali- the relatively low sensitivity of standard procedures to provides real-time, high-resolution, fornia, Irvine School of Medicine. characterize pancreatic cysts as benign or cancerous volumetric images of organs and “While many of these lesions are benign, some means there is a significant need for an effective, lowtissues, using a high-resolution cysts are precancerous and even cancerous, and cost, noninvasive diagnostic technique that can sigdisplay and proprietary software. need to be surgically removed. With current imag- nificantly improve patient outcomes and lower overall Photo courtesy of NinePoint Medical Inc. ing and sampling techniques, it remains difficult to treatment cost, the company said. confirm which patient has the high-risk or cancerFor more information, visit www.maunakeatech. ous type of cyst and whether surgery is strongly com. —Based on a press release from Mauna Kea Technologies advised. Needle-based optical biopsies may provide

FDA Issues 510(k) Clearance for AQ-Flex Miniprobe For Real-Time Optical Biopsy During EUS-FNA

F D A U P D AT E & P R O D U C T N E W S

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

Cologuard Colorectal Cancer Screening Test Assessed in Investigational Trial Preliminary analysis of the Cologuard colorectal cancer (CRC) screening test showed that it met or exceeded all primary and secondary end points in an investigational trial, according to a statement released by the testâ&#x20AC;&#x2122;s manufacturer, Exact Sciences. Cologuard is a multitarget CRC screening test for the detection of colorectal advanced adenomatous polyps and cancer. The test detects

Prototype of the Cologuard collection kit: The large white container is used to collect the stool sample, and the bracket holds the container on the toilet; the kit comes with a bottle of DNA stabilization buffer and an FIT component.

specific changes in a patientâ&#x20AC;&#x2122;s DNA that appear in the stool and are associated with the presence of CRC or precancerous polyps. The assay also identifies the presence of blood in the stool, another indicator of possible CRC. â&#x20AC;&#x153;There is a significant, unmet clinical need for an accurate, convenient, noninvasive colorectal cancer screening test,â&#x20AC;? said principal study investigator Thomas F. Imperiale, MD, professor of medicine and associate director for research, Division of Gastroenterology, Indiana University (IU) School of Medicine, and a member of the IU Simon Cancer Center, both in Indianapolis. â&#x20AC;&#x153;The data from the DeeP-C trial are very promising. Cologuard may well be a future solution for identifying slow-growing polyps, much before they develop into cancer.â&#x20AC;? The DeeP-C trial was designed to evaluate the Cologuard test for use in the detection of CRC and precancerous polyps. The trial comprised 10,000 patients aged between 50 and 84 years who were at average risk for CRC, including 64 patients with CRC and 752 patients with precancerous polyps. Enrollment was conducted at 90 sites to gain a broad demographic sampling of patients. The trial compared the

performance of the Cologuard test with colonoscopy and fecal immunochemical testing (FIT): The primary end points were sensitivity and specificity of the Cologuard screening test for CRC; secondary end points were sensitivity and specificity of the test for advanced adenomas, and noninferiority of Cologuard with respect to FIT for cancer sensitivity and superiority to FIT for advanced adenoma sensitivity. Each patient result from the Cologuard test was compared with the patientâ&#x20AC;&#x2122;s colonoscopy result and the histologic diagnosis of any lesions that were discovered during colonoscopy and biopsied. Cologuard demonstrated a sensitivity of 92% for the detection of CRC and a sensitivity of 42% for the detection of precancerous polyps, including 66% sensitivity for polyps of at least 2 cm. The Cologuard screening test is an investigational device and is not available for sale in the United States. Exact Sciences will submit data from the DeeP-C trial to the FDA as part of its premarket approval submission. â&#x20AC;&#x201D;Based on a press release from Exact Sciences

Photo courtesy of Exact Sciences

Join the C l ev el an d C l i n i c Team

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Nutrition Gastroenterologist The Department of Gastroenterology in the Digestive Disease Institute is seeking a Board CertiďŹ ed Gastroenterologist with Nutrition experience to join the largest, physician-led, multidisciplinary nutrition support team in the country!

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Vice Chairman, Digestive Disease Institute Chairman, Gastroenterology and Hepatology

Director, Center for Human Nutrition

Academic appointments are available at the Cleveland Clinic Lerner College of Medicine of CWRU.

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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 • JUNE 2013

On May 3, Ethicon Endo-Surgery, Inc., announced the FDA premarket approval of the Sedasys System, the first computer-assisted, personalized sedation (CAPS) system. Sedasys is indicated for the IV administration of 1% (10 mg/mL) propofol (Diprivan, AstraZeneca) injectable emulsion for the initiation and maintenance of minimal to moderate sedation, as defined by the American Society of Anesthesiologists (ASA) Continuum of Depth of Sedation guidelines, in ASA physical status 1 and 2 patients aged 18 years or older who are undergoing colonoscopy and esophagogastroduodenoscopy procedures. “The Sedasys System will address the growing preference for propofol sedation in gastroenterology by more closely matching the skill level of the sedation delivery team with the actual requirements of less complex cases,” said principal investigator Daniel

Pambianco, MD, medical director, Charlottesville Medical Research, Charlottesville, Va., and paid consultant for Sedasys. “The technology will empower health care facilities to more effectively use their limited resources to deliver greater value in the increasingly resource-constrained U.S. health care environment.” Data included in the premarket application demonstrated that patients who received sedation with the Sedasys System experienced fewer and less significant oxygen desaturation events than patients in a control group who received traditional sedation with benzodiazepines and opioids. The data also showed patients who received sedation with the Sedasys System recovered from the effects of sedation faster, with 99% recovering within 10 minutes, compared with those in the control group. The company reported that patients were highly satisfied with sedation provided by the Sedasys

US Endoscopy Launches AquaShield Water Bottle System With CO2 Extension Tubing

Photo courtesy of US Endoscopy

In April, US Endoscopy announced the release of the AquaShield water bottle system with CO2 extension tubing. The new product is used in conjunction with an air or carbon dioxide (CO2) source to clean the lens of the endoscope during a procedure. “The AquaShield system with CO2 extension tubing offers a convenient solution to our customers

The AquaShield system has extended tubing that eliminates the need for extra pieces during procedures where CO2 is used.

using CO2 insufflation,” said Gulam Khan, president of US Endoscopy, in a statement. “This new line item eliminates the need for purchasing and setup of separate CO2 extension tubing, saving our customers time and money.” In procedures where CO2 is used, extension tubing is required to connect the water bottle cap to an insufflator or CO2 source. According to a statement by US Endoscopy, most water bottle systems on the market today require customers to stock and use two separate items: the water bottle cap and CO2 tubing. The new AquaShield system with extended tubing eliminates the need for these extra pieces. The disposable AquaShield water bottle system is a 24-hour use system that eliminates the need to reprocess or deal with lost or replacement components. It also proactively supports patient safety by reducing the risk for bacterial contamination that may remain in reusable systems, US Endoscopy said. —Based on a press release from US Endoscopy

System, and physicians were significantly more satisfied with administration of sedation they provided to patients in the Sedasys group compared with sedation provided to patients in the control group. The Sedasys System will be marketed by Sedasys, a division of Ethicon Endo-Surgery, Inc., which will offer the system to facilities where an anesthesia professional is immediately available for consultation or assistance. In addition to receiving device-specific training, the member of the physician-led team who is administering sedation must have training in the

management of cardiorespiratory effects of propofol. “Anesthesiologists and gastroenterologists were key participants in the development of the Sedasys System, and we believe the technology has the potential to improve the experiences of both the clinical team and the patient,” Dr. Pambianco said in a company press release. The Sedasys System is scheduled to launch on a limited basis beginning in 2014. Sedasys plans to conduct two postapproval studies to monitor the use of the technology in actual clinical practice. —Based on a press release from Ethicon Endo-Surgery, Inc.

Lubiprostone Approved for OpioidInduced Constipation The FDA has approved a supplemental new drug application for lubiprostone (Amitiza, Sucampo Pharmaceuticals and Takeda Pharmaceuticals) 24 mcg twice daily as the first oral medication for the treatment of opioid-induced constipation (OIC) in adult patients with chronic noncancer pain (CNCP). Lubiprostone also is approved in the United States for the treatment of chronic idiopathic constipation in adults and irritable bowel syndrome with constipation in adult women. Binding of opioids to peripheral opioid receptors in the gastrointestinal (GI) tract results in absorption of electrolytes, such as chloride, and subsequent reduction in small intestinal fluid. Additionally, activation of enteric opioid receptors results in abnormal GI motility. Together, these processes result in OIC, which is characterized by infrequent and incomplete evacuation of stool, hard stool consistency and straining associated with bowel movements. Approximately 40% to 80% of patients taking opioids for CNCP report constipation. Some patients may discontinue opioid therapy and thereby endure pain rather than suffer from the constipation caused by opioids. Lubiprostone is a specific activator of ClC-2 chloride channels in the intestinal epithelium, thereby bypassing the antisecretory action of opiates. The approval of lubiprostone is based on results from Phase III studies of 12 weeks’ duration in patients taking opioids (among them, morphine, oxycodone and fentanyl) for CNCP, as well as a long-term, open-label safety study, which provided additional support for use in this population. Two of the Phase III studies met their overall efficacy end point, whereas a third Phase III study did not. The effectiveness of lubiprostone in the treatment of OIC in patients taking diphenylheptane opioids (e.g., methadone) has not been established. In clinical trials of lubiprostone versus placebo, the most common adverse reactions were nausea and diarrhea. Full prescribing information for Amitiza can be found at www.amitiza.com. —Based on a press release from Sucampo and Takeda

Photo courtesy of Takeda Pharmaceuticals

Sedasys System Approved for Administration of Sedation In Upper GI Endoscopy and Colonoscopy Procedures

Photo courtesy of Ethicon Endo-Surgery, Inc.

NEW PRODUCT ANNOUNCEMENT

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2013

Prometheus Launches New Adalimumab Drug And Antibody Levels Monitoring Test Prometheus Laboratories Inc., recently announced the U.S. market launch of its proprietary new test, Prometheus® Anser™ ADA. This novel test is designed to help identify potential causes of loss of treatment response in patients with inflammatory bowel disease (IBD) who are taking adalimumab (Humira, Abbott Laboratories). The launch of Prometheus® Anser™ ADA, which uses Prometheus’ proprietary homogeneous mobility shift assay, follows the July 2012 introduction of Prometheus® Anser™ IFX for infliximab monitoring (Remicade, Janssen Biotech, Inc.), further expanding the line of tests that target biologic agents being used to treat a variety of autoimmune diseases. Prometheus® Anser™ ADA measures adalimumab and adalimumab antibody levels in one serum sample, helping physicians to identify potential causes of loss of treatment response and helping to guide clinical management decisions. Many patients with IBD will use a biologic agent like adalimumab to manage and control symptoms during the course of disease. However, biologic agents may lose their effectiveness over time, resulting in increased disease activity and high discontinuation rates. This loss of treatment response is typically the result of insufficient drug levels or development of antibodies to the biologic agent itself. Recent clinical studies have suggested that approximately 44% of patients with IBD who have lost response to adalimumab have antibodies to the drug (Wang SL et al. J Pharm Biomed Anal 2013;78-79;39-44). When a patient loses response to adalimumab, physicians typically try increasing the dose of the drug; however, depending on the underlying cause of loss of response, this may result in exposure to unnecessarily high doses of the drug and unnecessary expense. “Prometheus® Anser™ ADA marks the latest milestone in our ongoing commitment to developing diagnostics to help guide personalized treatment decisions for gastroenterologists, patients and health care providers,” said Anthony Yost, chief commercial officer of Prometheus.

“As the gastrointestinal health care community continues to further understand the long-term use of biologic agents in treating diseases like IBD, the need for comprehensive diagnostic tests like Prometheus® Anser™ ADA and Prometheus® Anser™ IFX becomes more critical, as does the value these novel assays offer in terms of

time and expense saved when response to adalimumab or infliximab is lost.” Prometheus is committed to improving lives through the development and commercialization of novel pharmaceutical and diagnostic products that enable physicians to provide greater individualized

Brief Summary Please consult Package Insert for full prescribing information.

patient care. Prometheus is a leader in applying the principles of personalized medicine to the diagnosis and treatment of gastrointestinal diseases. For more information about Prometheus, visit www.prometheuslabs.com.

the properties of the gel and may cause device malfunction.

Indication for Use Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, ﬁber therapy, antimotility medications). Contraindications Solesta is contraindicated in patients with the following conditions:

may damage or alter the product.

damage or alter the product. other infections should be in accordance with accepted medical practice and applicable local, state and federal requirements.

Warnings

Potential adverse events include: abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, abdominal rigidity, alopecia, anal abscess, anal ﬁssure, anal hemorrhage, anal prolapse, anal pruritus, anorectal discomfort, back

vascular occlusion. fecal incontinence, feces hard, fatigue, gastrointestinal motility disorder, gastrointestinal enlarged prostate. Precautions General pprecautions procedures and who have successfully completed a comprehensive training and

abscess, nausea, edema, pain, painful defecation, pelvic mass, perineal pain, proctalgia, rectal obstruction, rectal prolapse, rectal spasm, rectal tenesmus, rectovaginal septum

previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with

studies.

age of 18 years. breastfeeding women. Directions for Use of anorectal conditions and who have successfully completed a comprehensive training treatments, four weeks apart. Patient related precautions p

disorders. Please consult Package Insert for full directions for use and method of administration. How Supplied

required to achieve a satisfactory level of improvement in incontinence. Procedure related precautions p

Storage recommended. which could cause leakage of the gel. *Safety information presented in the Package Insert only includes data up to 18 months.

A significant achievement for patients with fecal incontinence (FI)...

A good day.

It’s no accident. Solesta: a unique treatment for FI • • • •

An injectable, biocompatible gel Nonsurgical, in-office procedure No anesthesia required May preclude need for more invasive surgical procedures

Find out more at solestainfo.com.

Indication Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg. diet, fiber therapy, anti-motility medications).

Number of episodes/14 days

Durable efficacy with Solesta 25

P=0.001

n=136

20 15 10

15.0

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8.6

6.2

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Important Safety Information about SOLESTA SOLESTA® (hyaluronic acid/dextranomer) is contraindicated in patients with active inflammatory bowel disease, immunodeficiency disorders or ongoing immunosuppressive therapy, previous radiation treatment to the pelvic area, significant mucosal or full thickness rectal prolapse, active anorectal conditions (including abscess, fissures, sepsis, bleeding, proctitis, or other infections), anorectal atresia, tumors, or malformation, rectocele, rectal varices, presence of existing implant (other than SOLESTA) in anorectal region, or allergy to hyaluronic acid-based products. SOLESTA must not be injected intravascularly as injection of SOLESTA into blood vessels may cause vascular occlusion. Injection in the midline of the anterior wall of the rectum should be avoided in men with an enlarged prostate. SOLESTA should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program on the SOLESTA injection procedure. The most common adverse reactions with SOLESTA (incidence >4%) in the clinical study were proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort. Please see brief summary of full Prescribing Information on following page. Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals, Inc. Solesta is a registered trademark of Q-Med AB. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. SOL 12/77-1

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

Pancreatic Exocrine Insufficiency Part 2 of 2: Monitoring Clinical Response to Treatment VIVEK KADIYALA, MD SHADEAH LAILA SULEIMAN DARWIN L. CONWELL, MD, MS Center for Pancreatic Disease Brigham and Women’s Hospital Division of Gastroenterology, Hepatology, and Endoscopy Harvard Medical School Boston, Massachusetts

n Part 2 of this 2-part review, monitoring clinical response to treatment in patients with pancreatic enzyme insufficiency (PEI) is

covered, as well as future directions in pancreatic enzyme replacement therapy (PERT).

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS •

JUNE 2013

Monitoring Clinical Response to PERT Initially, PERT should be adapted based on clinical response, measured in terms of energy utilization for growth and degree of steatorrhea.1 Follow-up and titration after initial PERT is vital to managing symptoms of PEI and improving patient quality of life. Therapy should be initiated at the lowest possible dose and gradually increased until the desired control of steatorrhea is obtained. Achieving recommended normal weight and height ranges—assessed using ageappropriate ideal body weight (IBW) or body mass indices—is associated with better pulmonary function in patients with cystic fibrosis (CF).1 The Cystic Fibrosis Foundation (CFF) has established the following nutritional categories based on IBW: adequately nourished (>90% IBW), underweight (85%-89% IBW), mildly malnourished (80%-84% IBW), moderately malnourished (75%-79% IBW), or severely malnourished (<75% IBW). Malnourished patients also may be identified using measurements of triceps skinfold and midarm circumference.2 A list of useful considerations in patients experiencing suboptimal response to PERT is outlined in Table 1.3 Poor response to therapy may be defined as continued abdominal complaints—such as bloating, flatus, abdominal pain, loose or frequent stools, or overt diarrhea—in conjunction with symptomatic steatorrhea and/or poor growth despite PERT. In patients with weight loss unrelated to caloric intake or malabsorption, or poor growth despite improved steatorrhea, alternative gastrointestinal disorders and diabetes mellitus should be considered. Notably, abdominal pain alone does not indicate the need for increased PERT dosage.3,4 Clinical response may be measured objectively through a 72-hour stool fat quantification. A study performed in pancreatic duct–ligated mini-pigs demonstrated that the N-benzoyl-tryrosyl para-aminobenzoic acid (NBT-PABA) test can be used to monitor the efficacy and kinetics of treatment, particularly the extent of protein digestion and the effect of protease enzyme replacement therapy on digestion.5 Additionally, researchers have studied the use of the 13C-mixed triglyceride breath test to evaluate PERT efficacy in 20 patients with chronic pancreatitis (CP) and malnutrition.6 Despite an adequate clinical response to PERT, some individuals continued to have abnormal breath results.6 When therapy was titrated upward to normalize breath test results, patient nutritional status also was normalized as measured by increases in body weight, serum concentrations of retinol binding protein, and prealbumin.6 Although the NBT-PABA assay and 13C-mixed triglyceride breath test are not currently available in the United States, evidence demonstrates

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Table 1. Treatment Strategies For Patients With Suboptimal Response to PERT3 Increase dosage

Decrease fat intake to 50 to 75 g/day

Check compliance (fecal chymotrypsin) Add proton pump inhibitor or H2-receptor antagonist Check expiration date of product

Check storage environment of product Ensure patient is receiving enzyme dose with snacks or milk Look for evidence of concurrent gastrointestinal disorder PERT, pancreatic enzyme replacement therapy

the benefit of adjusted dosing to target appropriate PERT dosing for PEI. If PEI is not adequately treated with standard treatment with reported therapeutic compliance, a 2- to 3-fold enzyme dose increase may improve clinical response.7 Changes in dosage or product may require an adjustment period of several days before implementing further titration.7 If doses exceed 2,500 lipase units per kilogram per meal, further investigation is warranted prior to dose escalation, as doses greater than 2,500 lipase units per kilogram per meal require caution.8-10 An alternative strategy to improve clinical response is to distribute nutrient intake across 5 to 6 small meals.7 When assessing clinical progress, variation in individual responses, enzyme products, and range of dosages are important considerations. Enzyme doses are routinely adjusted by the prescriber, based on persistent signs and symptoms of malabsorption or adverse effects. Although patients experiencing steatorrhea are often on lifelong PERT and become

Table 2. GI Comorbidities In Patients With PEI8 Bacterial overgrowth of the small intestine Biliary disease, cholestasis Celiac disease Crohn’s disease Enteric bacterial infection Lactose intolerance Parasite, especially giardiasis

a meal, concomitant administration of bicarbonate or gastric acid suppressive therapy, and prescribing a brand of enzyme with a different dissolution profile (eg, microspheres vs microtablets).14 The concurrent administration of PPIs or H2-receptor antagonists also may provide benefit when using immediate-release, non-coated preparations.15

IMPACT

COMORBIDITIES

Gastrointestinal comorbidities in patients with PEI may cause persistent abdominal symptoms that will not respond to increased doses of PERT. These comorbidities, listed in Table 2, may coexist with PEI as a result of CF or CP and should be considered in patients who exhibit inadequate response to therapeutic doses of PERT. For example, patients with bacterial overgrowth following gastric and intestinal resection; intestinal infection, such as giardiasis; or other intestinal absorption disorders may have severely impaired absorption requiring surgical intervention.8

CONSIDERATIONS Pseudomembranous colitis Short bowel syndrome GI, gastrointestinal; PEI, pancreatic enzyme insufficiency

familiar with the optimal dose required per meal, it is imperative to instruct patients not to adjust the dosage without the supervision of a health care practitioner.11,12 If symptoms persist, enzyme dosage may be inadequate or the preparation may not be appropriate for the individual. In most patients, enteric-coated microspheres are the most favorable therapeutic option because this formulation prevents the release and degradation of enzymes before reaching the duodenum. However, in patients with high gastric acidity, coated preparations that typically release enzymes when pH exceeds 5.5 still may fail to deliver enzymes to the duodenum. In other individuals, high acid levels may deactivate the replacement enzyme and reduce efficacy, potentially requiring supplementation with a PPI or H2-receptor antagonist.8,13 Occasionally, employing other strategies may improve response. These alternatives include the use of non–enteric-coated enzymes in combination with enteric-coated enzymes, the administration of only a portion of capsules halfway through

SPECIAL POPULATIONS

Special populations require further consideration regarding PERT based on the etiology of PEI, past surgeries, or underlying disorders. For example, patients with achlorhydria have been treated successfully with uncoated enzyme preparations.8 Patients who receive continuous acid suppressive therapy also may be able to use conventional non–enteric-coated pancrelipase formulations.16 Individuals who have undergone pancreatectomy should receive conventional entericcoated enzyme preparations17; Creon 72,000 units lipase per meal and 36,000 per snack has been shown to be effective in patients with PEI following pancreatic surgery.18 The use of PERT in patients receiving enteral feeding following gastrostomy is also of particular concern. Data concerning appropriate dosing and timing of PERT with different enteral nutritional supplementation are lacking; there is a need for further research to achieve evidence-based consensus on providing optimal enteral nutrition in conjunction with PERT.19,20 Although none of the currently approved enzyme preparations have been designed for delivery via gastrostomy, a recent study has demonstrated that the Creon spheres, mixed with baby food (pH <4.5), can effectively be delivered through 16 Fr and 18 Fr gastrostomy tubes without clogging or loss of lipase activity.20

ADHERENCE

PERT

AND

SELF-MANAGEMENT

In addition to clinical considerations that may compromise response to PERT, patient adherence is another challenge to achieving and maintaining

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optimal therapeutic outcomes. In accordance with the 2004 CFF consensus guidelines, the primary objectives of the health care team are to ensure optimal care, facilitate access to pertinent medical resources, coordinate care among specialists and primary care practitioners, and support quality of life and independence for each patient.21 Counseling and management of patients receiving PERT generally takes place in the setting of the CF center clinic visit and is undertaken by a multidisciplinary care team that includes physicians, nurses, pharmacists, and dietitians. Additional patient resources are provided by the manufacturers of individual preparations. Family members are in a pivotal position to offer support, contribute to the development of strong life-management skills, and serve as a positive influence on lifestyle choices.21 As PERT is required with every meal, PEI patients are confronted with an important daily commitment to manage their own health and prevent complications. The large quantity of capsules necessary for some patients may contribute to poor PERT adherence. Timing is also a concern, as patients may take their medication before, but not during or after a meal, or may unintentionally forget to take the medication altogether. To assist patients in adhering to demanding treatment regimens and dietary choices, the CFF has issued helpful educational tips that include “Grab ’N Go” ideas—ranging from high-fat deli meat and cheese roll-ups in an insulated cooler to trail mix and raisin bread that can be strategically stored—to cut down on preparation time when schedules are busy.22 Minimeals can also be prepared in advance and then frozen or reheated when necessary. Adding color to meals in the form of various fruits and vegetables ensures antioxidants are incorporated into the high-calorie diet. Similarly, enzymes can also be stored in coat pockets or a book bag to facilitate access when consuming these meals or snacks. Patients should be actively involved in monitoring their own progress and should be thoroughly educated regarding IBW ranges. Between regularly scheduled health care visits, individuals can record their own weight using a scale at home and can be trained to report significant weight loss and seek immediate medical attention when necessary. Dietary factors also may result in inadequate response to therapy. In patients with CF, excessive intake of fruit juice, observed most often in children, can cause loose stools due to carbohydrate malabsorption.23 Patients with PEI need to be aware of these complications and manage their diets accordingly. Another important counseling point pertains to the appropriate dosage of enzymes and dietary considerations; there often is

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a lack of awareness that enzymes should be administered with milk or small snacks in addition to regular meals.3 Communication between patients and health care providers will help to optimize PEI management. In contrast, deliberate misuse of and nonadherence to prescribed PERT can explain inadequate response in some patients and can be confirmed by measurement of fecal chymotrypsin; low activity is suggestive of insufficient enzyme intake. Poor adherence to PERT is more problematic in patients during adolescence and young adulthood.24 Young women, in particular, may resist taking full doses because of fear of gaining weight or distorted body image.3 Attention to special challenges confronting children and adolescents with CF, including rapid physical growth, can help facilitate the transition into adulthood and improve medication adherence.21 Additionally, depression or inadequate coping mechanisms may affect the willingness of patients to adhere to therapy; these patients may require medical attention to prevent interference with recommended therapy.3 The Figure represents a reasonable approach to the management of PEI based on the discussion presented here.

PERT: Past and Future As a part of ongoing health care reform and national efforts to regulate treatments, recent FDA mandates have been developed to establish and guarantee the safety and effectiveness of PERT. Additionally, new therapeutic options are being developed to provide more flexibility in managing patients with PEI with various clinical needs.

FDA MANDATES Predating the 1938 Food, Drug, and Cosmetic Act, pancreatic enzyme replacements were not subject to the battery of dose-ranging, efficacy, and safety studies that are currently required for marketed products.25 Under the 1938 labeling rules, enzyme products must contain at least 90% of the labeled amount. To meet this requirement, many capsules were overfilled by as much as 50% or more—based on lipase content—to account for deterioration over time and ensure that the preparations met 90% of the labeled potency on their expiration date.26 Although most products listed in the United States Pharmacopeia (USP) have a lower and an upper limit regulation, this requirement was previously not applicable to pancreatic enzyme replacement products that were listed in the USP prior to 2000.25 More recently, microencapsulated products have been marketed without formal FDA approval by claiming coverage under the 1938 regulations.27 Actions taken by

Pancreatic enzyme replacement therapy at initial recommended doses

Adequate response

Inadequate response • Steatorrhea • Poor weight gain in children or continued weight loss in adults

Check compliance

Adequate compliance

Inadequate compliance • Address poor compliance

Increase dose by small increments • Avoid exceeding maximum recommended dose

Adequate response

Inadequate response

Adjunct therapy with acid-suppressing agent

Adequate response • Continue trial • Monitor regularly

Inadequate response

Recheck diagnosis: • Check stool for Giardia lamblia • Perform serology test for celiac disease • Perform breath test for bacterial overgrowth • Consider liver diseases

If positive, treat with specific therapy

If negative, prescribe low-fat diet or substitute dietary fat with medium-chain triglycerides

Figure. Approach to pancreatic enzyme replacement therapy in patients with pancreatic exocrine insufficiency.34 Source: Australasian Pancreatic Club

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manufacturers to meet labeling regulations may have compromised patient outcomes. Additionally, variations between capsules, batches, and brands have resulted in an inconsistent absorption pattern among patients with CF. This variability may be magnified with the use of H2-receptor blocking agents or PPIs to decrease gastric pH.26 A study of actual lipase activity demonstrated marked variability, providing evidence that product labels frequently misrepresented efficacy and were inaccurate when labeled potency was compared with actual content.27 In 1985, the FDA reconsidered the recommendation of the Advisory Review Panel on OTC Miscellaneous Internal Drug Products that pancreatic enzyme replacements be considered safe, effective, and accurately branded.28 These data were reviewed, and written comments, objections, and requests for oral hearings on the proposed rule-making were heard.28 Based on the information received, the FDA launched an investigation of pancreatic replacement enzymes and found inconsistencies in the formulation, dosage, and manufacturing processes of enzymes that could compromise safety and efficacy.29 The Federal Register in 1991 reported that over-the-counter products used to treat PEI were misbranded and could not be considered safe and effective because of bioavailability issues.28 In a 2008 review, the CFF expanded the use of generic pancreatic enzyme replacement products.1 The CFF concluded that there was insufficient evidence to support the efficacy of generic pancreatic enzyme preparations and highlighted the need for well-designed studies of PERT preparations, dosing, and clinical outcomes.1 Furthermore, due to a lack of evidence for generic products, the CFF recommended the use of proprietary pancreatic enzyme preparations for PERT.1 In response to a number of complaints directed at the inconsistency among enzyme replacement products and the lack of scientific data on these agents, the FDA published a notice in the Federal Register in 2004 stating that the manufacturers of all existing pancreatic enzyme replacement products must submit New Drug Applications under FDA scrutiny, demonstrate adequate safety and efficacy of each

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product, and receive FDA approval by 2008 in order to remain on the market.28 This deadline was subsequently extended to April 2010 to enable the highly anticipated data on safety and tolerability to be properly collected. At press time, 6 pancreatic enzyme preparations have received FDA approval and are commercially available.

EMERGING PERT OPTIONS There are currently several treatments and management strategies being evaluated to address the challenges in enzyme delivery and efficacy. The current pancreatic enzyme replacement products are porcine products; however, a microbial-derived preparation as well as human recombinant lipases may provide superior safety and resistance to acid and protease degradation. Microbial-derived liprotamase has been shown to be safe and effective in a Phase 3 trial of CF patients with PEI 7 years of age and older.30 Kiobrina, a recombinant human bile-salt stimulated lipase, is currently undergoing Phase 3 clinical trials in preterm (younger than 32 weeks) infants (ClinicalTrials. gov NCT01413581).31 Another approach being investigated is the use of engineered functional dietary lipids that can be more effectively digested and absorbed by patients with PEI. Modification of the substrateâ&#x20AC;&#x201D;specifically lipid droplet size, droplet surface composition, and fatty acid glycerol backbone esterificationâ&#x20AC;&#x201D;may improve lipase function.32,33

Conclusion Loss of pancreatic function in patients with CF, CP, or other disorders is associated with digestive malabsorption and associated clinical manifestations. Accurate diagnosis of PEI in at-risk individuals enables initiation of PERT according to established recommendations for dosing and administration. Close and frequent monitoring of clinical response and adherence must be performed along with the implementation of treatment modifications, dietary management, and patient counseling to effectively reduce symptoms, maintain growth and nutrition, improve quality of life, and reduce complications and mortality.

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Shlieout G, Koerner A, Maffert M, et al. Administration of CREON(R) pancrelipase pellets via gastrostomy tube is feasible with no loss of gastric resistance or lipase activity: an in vitro study. Clin Drug Invest. 2011;31(7):e1-e7.

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Yankaskas JR, Marshall BC, Sufian B, et al. Cystic fibrosis adult care: consensus conference report. Chest. 2004;125(1 suppl): 1S-39S.

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Spisak J. Grab ‘N Go! Meal and snack ideas for people with CF on the run. www.cff.org/UploadedFiles/LivingWithCF/StayingHealthy/Diet/MealSnackIdeas/Grab%2020%20and%20go.pdf. Accessed March 25, 2013.

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Mosseler A, Bergemann J, Becker C, et al. NBT-PABA test to assess efficiency and kinetics of substituted proteolytic enzyme action in pancreatic duct ligated minipigs. J Anim Physiol Anim Nutr. (Berl) 2008;92(3):399-404.

Lifshitz F, Ament ME, Kleinman RE, et al. Role of juice carbohydrate malabsorption in chronic nonspecific diarrhea in children. J Pediatr. 1992;120(5):825-829.

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Dominguez-Munoz JE, Iglesias-Garcia J, Vilarino-Insua M, et al. C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2007;5(4):484-488.

Heubi J. Treatment of exocrine pancreatic insufficiency in cystic fibrosis patients. US Respiratory Disease. 2007;1(1):48-50. www. touchrespiratory.com/articles/treatment-exocrine-pancreaticinsufficiency-cystic-fibrosis-patients. Accessed March 25, 2013.

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Layer P, Keller J. Lipase supplementation therapy: standards, alternatives, and perspectives. Pancreas. 2003;26(1):1-7.

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US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry Exocrine Pancreatic Insufficiency Drug Products—Submitting NDAs. Draft Guidance. April 2004. www.fda.gov/ohrms/dockets/98fr/2003d-0206-gdl0001.pdf. Accessed March 25, 2013.

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Borowitz D, Stevens C, Brettman LR, et al. Liprotamase long-term safety and support of nutritional status in pancreatic-insufficient cystic fibrosis. J Pediatr Gastroenterol Nutr. 2012;54(2):248-257.

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A Prospective, Randomized, Double-Blind, Phase 3 Study Comparing rhBSSL and Placebo Added to Infant Formula or Pasteurized Breast Milk During 4 Weeks of Treatment in Preterm Infants Born Before Week 32 of Gestational Age. ClinicalTrials. gov NCT01413581. http://clinicaltrials.gov/show/NCT01413581. Accessed March 25, 2013.

Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108(5):832-839.

Ramsey BW, Farrell PM, Pencharz P. Nutritional assessment and management in cystic fibrosis: a consensus report. The Consensus Committee. Am J Clin Nutr. 1992;55(1):108-116.

Borowitz DS, Grand RJ, Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127(5):681-684.

Read NW, McFarlane A, Kinsman RI, et al. Effect of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels of neurotensin and enteroglucagon. Gastroenterology. 1984;86(2):274-280.

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Beker LT, Fink RJ, Shamsa FH, et al. Comparison of weight-based dosages of enteric-coated microtablet enzyme preparations in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 1994;19(2):191-197.

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Brady MS, Rickard K, Yu PL, et al. Effectiveness and safety of small vs. large doses of enteric coated pancreatic enzymes in reducing steatorrhea in children with cystic fibrosis: a prospective randomized study. Pediatr Pulmonol. 1991;10(2):79-85.

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Proesmans M, De Boeck K. Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Eur J Pediatr. 2003;162(11):760-763.

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Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol. 2006;41(1):35-49.

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Layer P. [Intestinal regulation of pancreatic enzyme secretion: stimulatory and inhibitory mechanisms]. Z Gastroenterol. 1992;30(7):495-497.

Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clin Exp Gastroenterol. 2011;4:55-73.

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Giuliano CA, Dehoorne-Smith ML, Kale-Pradhan PB. Pancreatic enzyme products: digesting the changes. Ann Pharmacother. 2011;45(5):658-666.

Singh H, Ye A, Horne D. Structuring food emulsions in the gastrointestinal tract to modify lipid digestion. Prog Lipid Res. 2009;48(2):92-100.

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Whitcomb DC, Lehman GA, Vasileva G, et al. Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial. Am J Gastroenterol. 2010;105(10):2276-2286.

Toouli J, Biankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Med J Aust. 2010;193(8):461-467.

AUTHOR DISCLOSURES—Drs. Conwell and Ms. Suleiman and have no conﬂicts of interest.

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and