The Changing Landscape of IBD: Emerging Concepts in Patient Management

Changing Landscape of Inflammatory Bowel Disease

Faculty

Raymond K. Cross, MD, MS Professor of Medicine Director, Inflammatory Bowel Disease Program University of Maryland School of Medicine Co-Director, Digestive Health Center University of Maryland Medical Center Baltimore, Maryland

Dr. Raymond K. Cross is a board-certified Gastroenterologist and Professor of Medicine, Division of Gastroenterology and Hepatology, at the University of Maryland School of Medicine in Baltimore, Maryland.

He also serves as Director of the Inflammatory Bowel Disease Program at the University of Maryland School of Medicine in Baltimore (UMB) and is Co-Director of the Digestive Health Center at the University of Maryland Medical Center in Baltimore.

Dr. Cross is a Fellow of the American Gastroenterological Association and a member of the American College of Gastroenterology and Crohn’s and Colitis Foundation of America (CCFA). He is the past Chair of the Patient Education Committee and current Chair of the Clinical Awards Committee of the CCFA. He is also a member of the Mission Committee of the Maryland and Delaware Chapter of the CCFA. Dr. Cross received his undergraduate degree from Washington and Jefferson College in Washington, Pennsylvania, and his medical degree from the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania. He completed his postgraduate training in Internal Medicine at the University of Maryland and Baltimore VA Medical Centers in Baltimore, Maryland, where he was chosen as Chief Resident. He performed his Gastroenterology fellowship also at the University of Maryland and Baltimore VA Medical Centers in Baltimore. In addition, Dr. Cross has obtained a Master of Science degree in Clinical Research at the University of Maryland School of Medicine, Department of Epidemiology and Preventive Medicine, in Baltimore.

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Gary R. Lichtenstein, MD Professor of Medicine Director, Center for Inflammatory Bowel Diseases The Raymond and Ruth Perelman School of Medicine University of Pennsylvania Hospital of the University of Pennsylvania Gastroenterology Division, Department of Internal Medicine Perelman Center for Advanced Medicine Philadelphia, Pennsylvania

Dr. Gary R. Lichtenstein is the Director of the Inflammatory Bowel Disease Center and a Professor of Medicine in the Gastrointestinal Division of the Department of Medicine at the Hospital of the University of Pennsylvania and the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania.

Dr. Lichtenstein earned his medical degree from the Mount Sinai School of Medicine, New York, New York. He then completed his internship and residency in Internal Medicine at Duke University Medical Center, Durham, North Carolina, and a fellowship in Gastroenterology at the Hospital of the University of Pennsylvania School of Medicine. His current research interests encompass investigational therapies for the treatment of ulcerative colitis and Crohn's disease. Dr. Lichtenstein has received numerous research grants focusing on these areas and has served as the national/ international principal investigator evaluating novel agents for therapeutic trials in the treatment of ulcerative colitis and Crohn's disease.

A Fellow of the American Gastroenterological Association, the American College of Physicians, and the American College of Gastroenterology, he has served as Medical Secretary for the American Board of Internal Medicine, Gastroenterology Section. He holds membership and committee positions in many professional societies at a national level, including the American Gastroenterological Association, where he has served as chair and vice-chair of the clinical practice committee and as vice-chair of the practice economics committee; the American Society for Gastrointestinal Endoscopy, where he has served on the committee on training; the American College of Gastroenterology, where he has served on the Education, Programs, Nominations, and Research Committees and has chaired the abstract review committee for Inflammatory 2

Bowel Disease. He is also a member of the Crohn's and Colitis Foundation of America, where he served as the chair of the national membership committee of the Clinical Research Alliance, as well as on the national grants review committee and the national physician education committee. Additionally, he is a long-standing member of the American College of Physicians and the American Medical Association.

Dr. Lichtenstein’s numerous awards include the Louis A. Duhring Award for top specialist in the University of Pennsylvania Health system; the Christian R. and Mary F. Lindback Award for the top teacher in the University of Pennsylvania; the Penn Pearls Award for medical school teaching; the Donald B. Martin Teaching Award for the Department of Medicine House Staff teaching; and the Sidney Cohen Teaching Award for the Gastroenterology Division. He is listed in The Best Doctors in America for Inflammatory Bowel Disease and in Philadelphia Magazine among top gastroenterologists for elderly in Philadelphia and among top gastroenterologists in Philadelphia (Special Focus: Inflammatory Bowel Disease). He is the recipient of the Crohn's and Colitis Foundation of America (CCFA) Physician of the Year Award: Philadelphia and Delaware Valley Chapters.

In addition to having served on the editorial boards of the journals Gastroenterology, American Journal of Gastroenterology, Inflammatory Bowel Diseases, World Journal of Gastroenterology, and Digestive Diseases and Sciences, Dr. Lichtenstein served as a writer and section editor of Selected Summaries and as section editor of Print and Media Review in Gastroenterology for a 5-year term. He also has served and currently serves as a reviewer for such journals as The New England Journal of Medicine, Gastroenterology, The Lancet, Annals of Internal Medicine, Gut, Journal of Parenteral and Enteral Nutrition, American Journal of Gastroenterology, World Journal of Gastroenterology, and Journal of Clinical Gastroenterology. He is the executive editor of a newly PubMed-indexed journal, Gastroenterology and Hepatology; associate editor of Therapeutic Advances in Gastroenterology, The Physician and Sportsmedicine, Clinical Investigation; and Assistant Editor-in-Chief of the World Journal of Gastroenterology. An invited lecturer at the local, national, and international levels, Dr. Lichtenstein is the author or coauthor of more than 250 peer-reviewed primary articles, chapters, letters, and editorials, and has presented over 250 abstracts and edited 18 books. He has lectured at a national and an international level at over 300 invited conferences, symposiums, and institutional grand rounds.

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Preamble Target Audience This activity is intended for clinical gastroenterologists and specialist nurse practitioners/physician assistants involved in the treatment of patients with inflammatory bowel disease (IBD).

Educational Objectives After completing this activity, the participant should be better able to: • Evaluate disease risk and identify individuals who are likely to benefit from biologic or targeted synthetic therapy • Tailor management regimens for patients with IBD using a treat-to-target approach that reflects disease severity, treatment goals, therapeutic responses, and patient preferences • Partner with patients to provide IBD disease state education, promote shared clinical decision-making, encourage self-management efforts, and personalize long-term care • Discuss the cytokine networks underlying IBD pathophysiology, with a focus on newer mechanisms of action • Review mechanisms of current and novel non–tumor necrosis factor biologic and targeted synthetic therapies for the treatment of IBD

Program Overview In the past 2 decades, the introduction of biologic therapies that target underlying disease processes has dramatically changed the treatment of the inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn’s disease. Current biologic therapy with tumor necrosis factor inhibitors and anti-integrins has improved the treatment of IBD flares and maintenance of clinical remission. These agents are, however, limited by primary nonresponse and loss of response in a substantial proportion of patients, disease relapse after cessation of therapy, immunogenicity, and adverse effects such as risk for infection and malignancy.1 As the pathogenesis and treatment of IBD are complex and variable, there is a need to better understand the underlying pathogenic mechanisms and develop drug therapies to target these mechanisms.1 Geared to the needs of gastroenterologists, this IBD eHealth program includes an update on patient assessment and treat-to-target goals, as well as a review of best practices in shared decision-making in 4

treatment decisions for induction and maintenance of remission. In addition, the immunopathogenesis of IBD is discussed in the context of current and emerging targeted therapies for moderate to severe disease.

Reference 1.

Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38(2):127-142.

Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers, and other individuals and their spouses/life partners who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Raymond K. Cross, MD, MS Consultant/Independent Contractor: AbbVie Inc., Janssen Pharmaceuticals, Inc., LabCorp, Pfizer Inc., UCB, Inc; Grant/Research Support: AbbVie Inc. Gary R. Lichtenstein, MD Consultant: AbbVie Inc., Celgene Corporation, Eli Lilly and Company, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Luitpold Pharmaceuticals, Inc., Merck & Co., Pfizer Inc., Prometheus Laboratories Inc., Romark, L.C., Salix Pharmaceuticals, Inc., Shire Plc, Takeda Pharmaceuticals North America, Inc., UCB, Inc., Valeant Pharmaceuticals International, Inc.
 Grant/Research Support: Celgene Corporation, Janssen Pharmaceuticals, Inc., Salix Pharmaceuticals, Inc., Shire Plc, UCB, Inc., Valeant Pharmaceuticals International, Inc. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Lindsay Borvansky

Nothing to disclose

Andrea Funk

Nothing to disclose

Liddy Knight

Nothing to disclose

Kayla Messer

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Julia Muino

Nothing to disclose

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

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Physician Credit Designation Global Education Group designates this Live series for a maximum of 1.0 AMA PRA Category 1 Credit™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Global Education Group (Global) and Integritas Communications do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Instructions to Receive Credit In order to receive credit for this activity, the participant must complete the posttest and program evaluation.

Your posttest will automatically be graded. If you successfully complete the posttest (score of 70% or higher), your statement of participation will be made available immediately. Click on the View Statement of Participation link and print the statement for your records. If you receive a score lower than 70%, you will receive a message notifying you that you did not pass the posttest. You will have 2 opportunities to pass the posttest.

For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

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Introduction

The burden of Crohn’s disease and ulcerative colitis is significant and wide-ranging, affecting approximately 1.6 to 1.8 million Americans.1 When poorly controlled, these inflammatory bowel diseases (IBDs) negatively affect patient quality of life, social activities, travel, and ability to work, leading to higher rates of absenteeism and permanent work disability.2,3 Over the past 2 decades, the introduction of biologic therapies that target underlying disease processes has dramatically changed the treatment of IBD. Current biologic therapy with tumor necrosis factor ι inhibitors (infliximab, adalimumab, golimumab, and certolizumab pegol) and antiintegrins (natalizumab and vedolizumab) has improved the treatment of IBD flares and maintenance of clinical remission. These agents are, however, limited by primary nonresponse and loss of response in a substantial proportion of patients, disease relapse after cessation of therapy, and adverse effects such as risk for VIDEO 1: Introduction
 infection and malignancy.4 As the pathogenesis Gary R. Lichtenstein, MD and treatment of IBD are complex and variable, there is a need to better understand the underlying pathogenic mechanisms and develop drug therapies to target these mechanisms.4

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References 1.

2.

Dahlhamer JM, Zammitti EP, Ward BW, Wheaton AG, Croft JB. Prevalence of Inflammatory Bowel Disease Among Adults Aged ≼18 Years — United States, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(42):1166-1169.

Gunnarsson C, Chen J, Rizzo JA, Ladapo JA, Naim A, Lofland JH. The employee absenteeism costs of inflammatory bowel disease: evidence from US National Survey Data. J Occup Environ Med. 2013;55(4):393-401.

3.

Moradkhani A, Beckman LJ, Tabibian JH. Health-related quality of life in inflammatory bowel disease: psychosocial, clinical, socioeconomic, and demographic predictors. J Crohns Colitis. 2013;7(6):467-473.

4.

Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38(2):127-142.

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Chapter 1: Assessment Strategies and Treatment Goals in IBD

Raymond K. Cross, MD, MS To estimate current disease activity and the long-term risk for a disabling disease course in a patient with inflammatory bowel disease (IBD), a comprehensive assessment of symptoms and inflammatory activity through serum and fecal biomarkers, together with endoscopy and biopsy, is needed.

Initial Assessment In Crohn’s disease (CD), the clinical assessment should focus on the cardinal symptoms of abdominal pain, diarrhea, and fatigue in addition to such symptoms as weight loss, fever and, in children, growth failure.

Diagnosis of CD is made clinically and confirmed by evidence of active chronic intestinal inflammation on endoscopic and histologic assessment.1 Clinical assessment for ulcerative colitis (UC) focuses initially on diarrhea, rectal bleeding, tenesmus, and fatigue, along with other signs and symptoms that may include weight loss; arthropathy; and dermatologic, ocular, and hepatobiliary disease. Stool examinations with microbiologic studies are needed to rule out infectious causes of a patient’s symptoms.2 Endoscopic assessment (sigmoidoscopy or full colonoscopy) is essential to assess for inflammation and mucosal changes in both CD and UC. Understanding the disease distribution based on endoscopic and histologic findings has implications for colorectal cancer screening and disease prognosis and, ultimately, affects treatment decisions.3 When the inflamed area is not accessible with a standard colonoscope, computed tomographic (CT) enterography, magnetic resonance enterography (MRE), or even capsule endoscopy can be used to help assess inflammation or improvement or healing after treatment initiation.3 Initially, small bowel imaging can be helpful to determine the presence of small bowel involvement and, thus, differentiate CD from UC.1,2 9

Mucosal changes on endoscopy suggestive of CD include mucosal nodularity, edema, ulcerations, friability, and stenosis. When inflammation is confined to the colon, CD can be distinguished from UC by the presence of discontinuous involvement, with skip areas; sparing of the rectum; deep, linear, serpiginous ulcers of the colon; strictures; fistulas; or granulomatous inflammation.1 Endoscopy with biopsy is essential to identify mucosal changes characteristic of UC, such as loss of the typical vascular pattern, as well as granularity, friability, and ulceration.2 These changes typically are present in the rectum and proceed proximally in a symmetric, continuous, and circumferential pattern into the colon, though isolated cecal inflammation may also be present. Patients who have previously been treated for UC may exhibit skip areas and rectal sparing.2 Sigmoidoscopy is typically sufficient to confirm the presence of inflammation, obtain biopsy specimens, and exclude other causes of colitis, such as cytomegalovirus. The choice of colonoscopy versus sigmoidoscopy depends on patient preference for oral versus rectal bowel preparation or sedation versus no sedation. The presence of severe inflammation will likely prevent completion of a full colonoscopy due to the increased risk for perforation.

Laboratory assessment of inflammation in IBD includes a complete blood count, with measurement of hemoglobin, quantitative C-reactive protein (CRP), and a comprehensive metabolic panel that includes serum albumin. CRP has some limitations in this setting, as it is a nonspecific marker of inflammation in the body and normal CRP levels can be found in as much as 40% of patients despite the presence of inflammation.1 Although the newer biomarkers fecal calprotectin and fecal lactoferrin are gut-specific markers of inflammation, they cannot be used to determine the etiology of the inflammation (eg, CD, UC, or infection).1

Disease Severity Disease severity is a fundamental factor guiding treatment and has an effect on timing and choice of therapies. Disease severity refers to the severity of symptoms or inflammation at a point in time.

Disease severity should be distinguished from prognosis, which predicts a patient’s long-term risk for a more severe or disabling disease course.

Numerous tools are available for assessing symptoms, quality of life, patient-reported outcomes (PROs), and endoscopic disease activity; these, together with cross-sectional imaging and histologic disease activity (in UC). All are, however, single point-in-time estimates and each has limitations.4 Efforts are ongoing to develop an overall disease severity index that can more reliably categorize disease severity.4,5

VIDEO 2: Crohn’s Disease, Ulcerative Colitis, and Smoking Raymond K. Cross, MD, MS

The current treat-to-target approach requires a quantifiable assessment of disease severity, using available indices to monitor response to treatment. Symptom-based categorization of disease severity can be erroneous, particularly in patients with CD who may have no obvious clinical symptoms but whose histologic examination demonstrates severe inflammation or, conversely, patients who report very severe symptoms 10

but have no evidence of inflammation.4 Commonly used IBD disease severity indices that are also included in the current American College of Gastroenterology (ACG) IBD management guidelines are listed in Table 1.1.1,2 These indices are composite scores based on factors such as number of loose stools, frequency of rectal bleeding, laboratory values, sigmoidoscopic appearance, and physician global assessment.2 Despite widespread use in clinical trials, these indices have some limitations. For example, indices for UC do not account for symptoms of abdominal pain, fatigue, or fear of episodes of incontinence, which are often of greatest concern to patients with UC.2 Patient-reported outcome indices should be combined with an objective measure such as a serum or fecal biomarker, with or without endoscopy.

Risk Stratification Risk stratification in IBD is aimed at determining the best course of therapy based on a patient’s risk of requiring colectomy (in UC) or developing severe disease (in CD; stricture, fistula, and abscess leading to hospitalization and surgery).7,8 The objective is to identify these high-risk patients early in their disease course and initiate a highly effective therapy, such as a biologic or new small-molecule agent.

The American Gastroenterological Association (AGA) clinical decision support tools for CD and UC are used to risk-stratify patients and recommend initial treatments based on low- or high-risk status, with modification over time based on change in clinical variables and response to therapy. These tools reflect common clinical scenarios in which more than one approach is reasonable and evidence as to the single best treatment is lacking.

A top-level overview of each decision algorithm is provided in Figures 1.1 and 1.2. Therapy for CD has shifted away from mesalamine and antibiotics for low-risk patients and corticosteroids, azathioprine, and methotrexate for patients with moderate-tosevere disease (Figure 1.1).

VIDEO 3: Corticosteroids in IBD
 Gary R. Lichtenstein, MD

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The current approach is to use budesonide, corticosteroids, and azathioprine for low-risk patients and biologic therapy with tumor necrosis factor (TNF) antagonists (ideally in combination with azathioprine) or integrin antagonists for high-risk patients.7 Although ustekinumab was approved by the US Food and Drug Administration (FDA) for use in CD after the algorithm was published, it is reasonable to include ustekinumab as a treatment for high-risk patients as well; the 2018 American College of Gastroenterology clinical guidelines published in 2018 recommend the use of ustekinumab in patients with moderate-to-severe CD for whom previous treatment with corticosteroids, thiopurines, methotrexate, or anti-TNF inhibitors failed, or who 13

have had no prior exposure to anti-TNF inhibitors.1 Options recommended for low-risk patients with UC include oral and rectal 5-aminosalicylate (5-ASA), budesonide, corticosteroids, and azathioprine (Figure 1.2).

Treatment options for high-risk patients with UC include corticosteroids as bridge therapy to thiopurines, anti-TNF therapy with or without concomitant immunomodulators, or vedolizumab with or without concomitant immunomodulators.8 Tofacitinib, a pan–Janus kinase (JAK) inhibitor, was FDA-approved for UC after publication of the AGA care pathway, but it would be another reasonable choice for high-risk patients.

Treat to Target and Tight Disease Control Management of IBD has expanded beyond simply alleviating symptoms and improving quality of life to achieving clinical, biologic, and endoscopic remission (ie, deep remission), with the goal of preventing disease progression, bowel damage, surgery, and disability. Very deep remission describes clinical, biologic, and endoscopic remission with normalized histology. Early initiation of treatment to prevent bowel damage, treating to target, and tight disease control with therapeutic monitoring are tenets of current IBD management.9 Treat-to-target approaches involve assessing patients via endoscopy prior to making treatment decisions, instituting a change in therapy for symptomatic disease with objective evidence of inflammation, and reassessing within 6 months to ensure that deep remission is achieved.10,11 While the AGA recommends specific treatment targets, the choice of treatment target should also reflect the patient’s treatment goals, preferences, therapeutic response, and available treatment options. The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) guidelines recommend treatment targets that include clinical and patient-reported symptom improvement together with mucosal healing (Table 1.2).10 Histologic remission is an adjunctive target in UC, whereas CRP and fecal calprotectin are adjunctive targets in CD. The STRIDE recommendations note that CRP or fecal calprotectin levels that do not normalize with treatment should prompt further endoscopic evaluation, regardless of symptoms.

A 2017 proposal to revise the STRIDE recommendations included incorporating the gut-specific biomarker of inflammation, fecal calprotectin, as a treatment target (not adjunctive target) for both types of IBD.12 The CALM trial found better clinical and biochemical outcomes in patients with moderate-to-severe CD managed with a tight control algorithm that included CRP and fecal calprotectin than in patients with symptom-driven 14

decision-making.13 Two randomized controlled trials in patients with UC showed that increasing the 5-ASA dosage in patients in clinical remission but with elevated fecal calprotectin levels lowered the fecal calprotectin levels below 200 μg/g, a cutoff associated with lower rates of clinical relapse.14,15

Key Clinical Highlights • Although numerous tools are available to gastroenterologists to comprehensively assess a patient with IBD, all are single point-in-time estimates and each has limitations.

• The current treat-to-target approach requires quantifiable assessment of disease severity, using available indices to monitor response to treatment.

• The objective of risk stratification is to identify high-risk patients early in their disease course and initiate a highly effective therapy, such as a biologic or new small-molecule agent.

References 1.

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4.

5.

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Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113(4):481-517.

Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol.

2010;105(3):501-523; quiz 524.

Peyrin-Biroulet L, Panés J, Sandborn WJ, et al. Defining disease severity in inflammatory bowel diseases: current and future directions. Clin Gastroenterol Hepatol. 2016;14(3):348-354.e317.

Siegel CA, Whitman CB, Spiegel BMR, et al. Development of an index to define overall disease severity in IBD. Gut. 2018;67(2):244-254.

Khanna R, Zou G, D’Haens G, et al. A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn’s disease activity. Aliment Pharmacol Ther. 2015;41(1):77-86.

Jairath V, Khanna R, Zou GY, et al. Development of interim patient-reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials. Aliment Pharmacol Ther. 2015;42(10):1200-1210.

Sandborn WJ. Crohn’s disease evaluation and treatment: clinical decision tool. Gastroenterology. 2014;147(3):702-705.

Dassopoulos T, Cohen RD, Scherl EJ, Schwartz RM, Kosinski L, Regueiro MD. Ulcerative colitis care pathway.

Gastroenterology. 2015;149(1):238-245.

Colombel JF, Narula N, Peyrin-Biroulet L. Management strategies to improve outcomes of patients with inflammatory bowel diseases. Gastroenterology. 2017;152(2):351-361.e355.

Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324-1338.

Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13(6):1042-1050.e1042.

Pouillon L, Peyrin-Biroulet L. It is time to revise the STRIDE guidelines determining therapeutic goals for treat-to-target in inflammatory bowel disease. J Crohns Colitis. 2018;12(4):509.

Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390(10114):2779-2789.

Lasson A, Öhman L, Stotzer PO, et al. Pharmacological intervention based on fecal calprotectin levels in patients with ulcerative colitis at high risk of a relapse: a prospective, randomized, controlled study. United European Gastroenterol J. 2015;3(1):72-79.

Osterman MT, Aberra FN, Cross R, et al; DEAR Investigators. Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol. 2014;12(11):1887-1893.e3.

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Chapter 2: Best Practices in Tailoring Treatment of Moderate and Severe IBD Raymond K. Cross, MD, MS As with the assessment of inflammatory bowel disease (IBD), tailoring IBD treatment requires that clinicians continually integrate findings from clinical, biomarker, and endoscopic assessments into treatment plans.

Tailoring treatment to individual patient needs and preferences also is a key factor in success of IBD treatment.

Initiating Treatment for Moderate-to-Severe Disease The American Gastroenterological Association (AGA) clinical decision support tools described in Chapter 1 recommend that the initial therapy choices for Crohn’s disease (CD) and ulcerative colitis (UC) be informed by the patient’s risk status, based on inflammatory burden, disease characteristics, and comorbidities and complications related to disease or therapy (see Chapter 1, Figures 1.1 and 1.2).1,2 Because immunomodulator and biologic therapies used to treat IBD may increase susceptibility to and severity of infections, testing for certain latent and active infections and reviewing the patient’s immunization status are important.3,4 Testing for latent tuberculosis, hepatitis B, and thiopurine methyltransferase (TPMT) activity should be obtained early (ideally at or near diagnosis) so the information is available when the patient is ready to start an immune suppressant or biologic. In addition to testing for latent or active tuberculosis, other latent opportunistic infections may be relevant based on region, occupation, or other patient characteristics (eg, histoplasmosis or blastomycosis). TPMT genotyping or phenotyping will identify patients with absent or reduced TPMT activity at risk for severe myelotoxicity after initiation of thiopurine therapy.3,4

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Ideally, immunization status should be reviewed and vaccinations brought up-to-date in advance of starting immunomodulator or biologic therapy. Patients who are hepatitis B surface antigen–positive will need treatment with antiviral agents before starting therapy to prevent hepatitis B flares and liver failure. Patients who are seronegative for hepatitis B should be vaccinated with a recombinant vaccine. Other appropriate vaccinations include pneumococcal (PCV13 and PPSV23), varicella, human papillomavirus, influenza, hepatitis A, and herpes zoster. Patients using immunomodulator or biologic therapy should be advised to avoid live vaccines.3,4 It is important to acknowledge potential challenges associated with administering needed vaccines before starting therapy, as well as payer restrictions on such vaccines in young, nonimmune-suppressed individuals.

Tailoring Treatment Adjustments The treat-to-target approach using objective targets, as described in Chapter 1, and serial therapeutic adjustments as needed can help engage physicians and patients in shared decision-making regarding treatment options, particularly when a change of therapy is warranted.5 Through this process, physician and patient can come to agreement on defined trials of therapies, followed by objective assessment and reconsideration of treatments. Respect for patient autonomy and the use of objective markers of disease activity can foster trust and empower patients and physicians with valuable information to guide shared decisions about therapy choices.5 Therapeutic drug monitoring is essential for guiding the choice of biologic therapy when the patient’s disease does not respond to therapy or response wanes.6 The AGA Committee on Therapeutic Drug Monitoring outlines strategies to modify therapy in patients with no response, incomplete response, or loss of response, based on trough drug concentration and presence or absence of antidrug antibodies (Table 2.1).

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An objective assessment such as colonoscopy is warranted before switching agents in patients whose disease is not responding despite therapeutic drug level. Patients who are tolerating a given therapy should be objectively assessed for achievement of agreed-upon treatment targets, and consideration should be given to whether sufficient time has elapsed for the therapy to have taken effect. When response is poor after sufficient time on treatment or response has waned, physician and patient should discuss moving on to another medication if therapeutic options have not been exhausted. For patients with focal or complicated VIDEO 4: Discussing Colectomy With Patients disease transitioning to a different therapy, surgery Who Have UC should be a part of that discussion. Likewise, in Raymond K. Cross, MD, MS patients with UC, colectomy should be included as a treatment option at each step when medical therapy has failed. It is important to discuss the pros and cons of each option with the patient to identify the patient’s preferences and concerns about side effects, as well as which medications are on formulary for the patient’s health insurance.

Tailoring Therapy Through Shared Decision-Making In a shared decision-making process, physicians and patients arrive at treatment decisions together, informed by the best available evidence and the patient’s disease characteristics, values, and needs.7 Shared decision-making involves frank discussion about disease severity and prognosis, disclosure of all appropriate treatment options, and potential benefits and risks of each treatment for each patient. Shared decision-making can foster more productive discussions that help define a treatment course based on the patient’s specific risk factors, concerns, lifestyle, and the preferences of both patient and provider.5 Important to this shared decision-making is the patient’s understanding of the risks associated with advanced therapies. Evidence suggests that patients better understand absolute terms when presented with effectiveness and safety data. Statements such as “the medicine works in the majority of patients” or “the risk of lymphoma is twice as high with this drug than another drug” are less effective for patient understanding than “this biologic carries a risk for lymphoma of about 1 in 2500.”8,9 Putting this information in perspective by comparing it to another risk that is more familiar to patients, using visual displays and analogies, also may be helpful.9 For example, “the lifetime risk of a man developing prostate cancer is 1 in 9, and the lifetime risk of a woman developing breast cancer is 1 in 8.” Visual aids can help communicate these points to patients. A 10,000-people chart is a helpful tool for communicating disease susceptibility risk. If there are 10,000 dots and the risk for immune suppression–related lymphoma is 1 in 2500, the clinician would circle 4 dots to represent the risk (Figure 2.1). Treatment response can also be demonstrated visually: 60% of patients responding to treatment with a drug can be shown by shading 60% of a graph. Nurse educators and advanced practice nurses can be an excellent resource for these and other patient education activities.

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Studies in diabetes and other chronic diseases suggest that patients who have knowledge of their disease and objective goals for management may do better at self-managing their disease.11,12 It is essential that patients understand why a specific medication or treatment approach is recommended and the risks and alternatives of the recommended approach. This crossroads in management is a good opportunity to dispel patient and caregiver preconceived notions and set expectations for treatment. In 2018, the AGA launched the My IBD Manager app for smartphones, which allows patients to monitor their dosing and schedule treatments and supplements; track symptoms; and monitor daily fatigue, mood, ability to keep social plans, and general well-being. Together with the Ask AGA: IBD clinical platform for clinicians, patients can monitor their disease and share information with their health care providers.

A 2018 survey of more than 300 patients with IBD indicated they are most interested in education regarding medications, what to expect in the future, living with IBD, and dietary advice, with the topic of medication most frequently identified.13 Interestingly, topics such as causes, symptoms, and surgery, which are often addressed in traditional education programs, were ranked lower; patients said they prefer to receive education on these topics from specialist physicians or nurses.

For patients, weighing the benefits and risks of IBD therapies is particularly challenging, owing to factors such as wariness about immunosuppressive drugs, the abundant yet varying quality of medical information on the Internet, and widespread information sharing via news outlets and social media. Physicians can help patients make informed decisions by taking the time to identify and understand resistance to a given treatment recommendation and to direct patients to credible educational resources. An algorithm for shared decision-making regarding treatment choices is provided in Figure 2.2.5

19

Concluding Remarks In summary, challenges exist between providers and patients when immunosuppressive therapies are initiated or when patients are being referred for surgery. Many patients and their caregivers have preconceived negative perceptions of certain treatments because they lack education on them or have gotten misinformation from unreliable sources regarding their risks. The practicing gastroenterologist must engage in shared decision-making to properly inform patients of their treatment options and to develop a strong therapeutic relationship with patients. With the approval of multiple classes of effective treatments, as well as emerging treatment paradigms that emphasize earlier use of advanced therapies in high-risk patients and treating to objective markers of inflammation, the shared decision-making process can be daunting.

For the busy community gastroenterologist, we recommend that providers summarize treatment options into 3 categories: speed of onset of action, mode of delivery (oral, subcutaneous, or intravenous), and safety.

Patients can often prioritize what is most important to them so that the gastroenterologist can focus on 1 or 2 agents. For example, for a patient with UC who prefers an oral therapy, the patient-clinician discussion should focus on whether tofacitinib might be an appropriate choice, based on disease severity, efficacy and safety profiles, and factors related to treatment adherence. Development of practice-specific educational 20

materials and use of educational materials from valid sources can supplement the process. Also, many practices utilize nurse navigators or advanced practice providers to assist with shared decision-making.

Key Clinical Highlights • Tailoring treatment for IBD requires that clinicians continually integrate findings from clinical, biomarker, and endoscopic assessments into treatment plans.

• Tailoring treatment to individual patient needs and preferences is a key factor in successful IBD treatment.

• When discussing advanced therapies with patients, providers can summarize treatment options into 3 categories: speed of onset of action, mode of delivery (oral, subcutaneous, or intravenous), and safety.

References 1.

2.

3.

4.

5.

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7.

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Dassopoulos T, Cohen RD, Scherl EJ, Schwartz RM, Kosinski L, Regueiro MD. Ulcerative colitis care pathway.

Gastroenterology. 2015;149(1):238-245.

Sandborn WJ. Crohn’s disease evaluation and treatment: clinical decision tool. Gastroenterology. 2014;147(3):702-705.

Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol.

2010;105(3):501-523; quiz 524.

Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113(4):481-517.

Rubin DT, Krugliak Cleveland N. Using a treat-to-target management strategy to improve the doctor-patient relationship in inflammatory bowel disease. Am J Gastroenterol. 2015;110(9):1252-1256.

Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S; American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827-834.

Towle A, Godolphin W. Framework for teaching and learning informed shared decision making. BMJ. 1999;319(7212): 766-771.

Rogler G. Editorial: how to interpret risks and prediction of complications in Crohn’s disease—can our patients interpret them? Aliment Pharmacol Ther. 2016;43(5):651-652.

Galesic M, Garcia-Retamero R. Statistical numeracy for health: a cross-cultural comparison with probabilistic national samples. Arch Intern Med. 2010;170(5):462-468.

Siegel CA. Review article: explaining risks of inflammatory bowel disease therapy to patients. Aliment Pharmacol Ther.

2011;33(1):23-32.

Hibbard JH, Mahoney ER, Stock R, Tusler M. Do increases in patient activation result in improved self-management behaviors? Health Serv Res. 2007;42(4):1443-1463.

Sieber W, Newsome A, Lillie D. Promoting self-management in diabetes: efficacy of a collaborative care approach. Fam Syst Health. 2012;30(4):322-329.

McDermott E, Healy G, Mullen G, et al. Patient education in inflammatory bowel disease: a patient-centred, mixed methodology study. J Crohns Colitis. 2018;12(4):419-424.

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Chapter 3: Evolving Concepts in IBD Pathophysiology

Gary R. Lichtenstein, MD Although a complete understanding of the etiology of inflammatory bowel disease (IBD) remains elusive, we recognize that the 4 main components contributing to the disease process are1,2: • Genetic susceptibility of the host • A dysregulated immune response, leading to mucosal impairment • Abnormal gut microbiota • Environmental influences Genome-wide association studies have identified more than 200 susceptibility loci that confer risk VIDEO 5: Will Genes Guide Therapy for IBD? for IBD, including loci that are specific for Crohn’s Gary R. Lichtenstein, MD disease (CD), for ulcerative colitis (UC), or that are common to both. These susceptibility loci have been found on approximately 300 potential candidate genes.2 At present, several genes appear to have a more prominent role in the development of IBD, including the nucleotide oligomerization domain (NOD) 2 gene, the first gene identified in CD.2,3 Chronic NOD2-mediated immune stimulation is thought to be a factor controlling proinflammatory cytokine production. More recently, other genes identified as contributing to chronic inflammation in IBD include, but are not limited to, autophagy-related protein 16-1 (ATG16L1), the

22

interleukin (IL)-23 receptor gene, the IL-12B receptor gene, Janus kinase 2 (JAK2) gene, and signal transducer and activator of transcription 3 (STAT3).4 The gut microbiome (ie, the collective genomes of microorganisms residing within the human gastrointestinal tract5), plays an important role in maintaining intestinal homeostasis and developing and activating the host immune system.6 The gut microbiota, which comprises a community of ≈100 trillion microorganisms in the gastrointestinal tract, consists primarily of bacteria but also includes viruses, fungi, and protozoa.6 Abnormalities of gut microbiota (also known as dysbiosis) are present in IBD, either quantitatively (lower microbiota diversity) or qualitatively (disordered composition and functionality).7,8 The gut microbiota, which protects against pathogens and modulates the immune system, is increasingly recognized as an important factor connecting genes, environment, and the immune system.9 Genetic variations, medications, food ingredients, antibiotics, infection, smoking, and pesticides can adversely affect the gut microbiota.1,5,7 Environmental exposures early in life, such as mode of delivery at birth, diet, and hygiene, influence the makeup of a person’s intestinal microbiota.10

Gut Immune System Both CD and UC are immune-mediated diseases in which chronic inappropriate activation of the adaptive immune system against gut microorganisms appears to be a primary pathogenetic factor.4 Most gut organisms are either harmless or beneficial, aiding digestion and preventing pathogenic bacterial species from taking hold. The epithelial cell layer separating the intestinal immune system (Figure 3.1) from the lumen must remain intact to prevent invasion by pathogenic bacteria. Under noninflammatory conditions, Toll-like receptor (TLR) signaling downregulates pattern recognition receptors in response to luminal pathogens, thus promoting mucosal wound healing.4 In the inflammatory setting of IBD, impaired TLR signaling leads to increased permeability of the intestinal mucosa and inadequate mucosal healing, resulting in defective barrier function of the epithelium.4

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Cytokines control multiple aspects of the inflammatory response and play an important role in the pathogenesis of CD and UC. In these diseases, an imbalance between proinflammatory and anti-inflammatory cytokines hinders resolution of inflammation, which leads to breakdown of mucosal tissue.11 A host of different cells is involved in the development of intestinal inflammation, and various monoclonal antibodies can block these inflammatory activities. Patients with active IBD have an imbalance in the production of various cytokines, including tumor necrosis factor alpha (TNF-α). Other cytokines identified as having a role in IBD include IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, and

VIDEO 6: Unanswered Questions Regarding Biosimilars Gary R. Lichtenstein, MD

IL-23, and transforming growth factor beta (TGF-β).

Because the proinflammatory cytokine TNF plays a key role in chronic intestinal inflammation associated with IBD, the first biologic agents approved for use in IBD were aimed at neutralizing TNF (infliximab, adalimumab, certolizumab pegol [CD only] and golimumab [UC only]).12-15 Recent years have seen the introduction of biosimilars for the anti-TNF agents infliximab and adalimumab; these new agents represent similar copies of an approved original biologic reference drug.16 However, the failure of anti-TNF therapy in a substantial proportion of patients indicates that other inflammatory pathways are likely activated in these patients. Further advances in understanding the specific mechanisms of IBD pathogenesis follow.

Integrin-Cell Adhesion Molecule Pathway Homing of T lymphocytes to the gut is a key step in the pathogenesis of T-cell-dependent chronic intestinal inflammation,18 and infiltration of lymphocytes into the lamina propria at sites of inflammation is well documented in IBD.19 Integrins are adhesion mediators with a central role in leukocyte homing and cell differentiation in both homeostasis and inflammation.20 The integrins α4β1 and α4β7 mediate trafficking of leukocytes to the gut and other areas of inflammation. Gut-selective leukocyte homing is facilitated by interactions between α4β7 and its ligand, mucosal addressin cellular adhesion molecule-1 (MAdCAM-1); retention of lymphocytes in mucosal tissue is mediated by the ligand E-cadherin.20 Disrupting leukocyte trafficking to the gut by inhibiting adhesion molecules such as integrins and their receptors is a target of IBD therapy. The anti-integrin agent natalizumab is US Food and Drug Administration (FDA)-approved for use in CD and blocks α4β1- and α4β7-mediated trafficking to the gut and central nervous system.21,22 Natalizumab is not widely used because it carries a risk for progressive multifocal leukoencephalopathy. Vedolizumab, FDA-approved for both CD and UC, is a humanized monoclonal antibody that specifically antagonizes the α4β7 integrin by inhibiting its binding to gut-specific MAdCAM-1.23

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Interleukin Signaling Interleukin-23, one of the IL-12 family of cytokines, has an important role in adaptive immune responses: IL-23 is involved in the development of T-helper (Th) 17 cells, which are thought to be effector cells in IBD and whose number is increased in inflamed intestinal tissue of patients with IBD.24 IL-23 also inhibits regulatory T-cell responses in the intestine, thereby enhancing local inflammation.25 IL-12 and IL-23 share a common component, the p40 subunit, and agents that bind to this subunit prevent these cytokines from binding to the IL-12 receptor subunit beta 1, which in turn normalizes IL-12- and IL-23-mediated signaling, cellular activation, and cytokine production. The first anti-IL agent FDA-approved for CD, ustekinumab, targets the p40 subunit of IL-12 and IL-23, demonstrating the efficacy of IL-12 and IL-23 inhibition for downregulating intestinal inflammation.26 Newer research has suggested that IL-23 may be the more important cytokine to target in IBD, and current studies are focused on selectively blocking IL-23 by targeting its p19 subunit, which is not present on IL-12.25,27,28

Janus Kinase-Signal Transducer and Activator of Transcription Pathway The Janus kinases (JAKs) are a family of proteins discovered in the 1990s. Following the binding of specific cytokines (such as IL-2, IL-6, IL-11, IL-12, IL-23, interferon gamma [IFN-γ], IFN alpha [IFN-α], and erythropoietin) to their receptors, JAKs transmit signals to the nucleus through a series of steps that leads to their action as a docking site for signal transducers and activators of transcription (STATs). When docked, STATs are phosphorylated by the activated receptor-associated JAKs; eventually this transcription and translation produces proteins that mediate immune responses.29 The JAK-STAT pathway is an important mediator of inflammatory signals.30 The 4 JAKs (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) and the 7 STATs work together to influence many cytokine functions through activation of the JAK-STAT pathway.31 Inhibition of each JAK protein leads to inhibition of signaling of a specific subset of cytokines (Figure 3.2). Certain major inflammatory drivers (eg, TNF-α and IL-1) do not signal through the JAK pathway but are important because they induce expression of a wide range of downstream proinflammatory cytokines that, in turn, depend on JAK signaling.30 Owing to the known relevance of the JAK-STAT pathway in inflammation pathogenesis, research focused on targeting different aspects of this signaling pathway as treatment options in IBD. The first JAK inhibitor FDAapproved for UC (tofacitinib) inhibits JAK1, JAK2, and JAK3. By directly and indirectly modulating IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, this agent demonstrates proof of concept for inhibiting JAK signaling as treatment for IBD.32 The clinical relevance of selective JAK inhibition (JAK1 vs JAK2 vs JAK3) is not yet clear, but ongoing studies of the JAK inhibitor agents filgotinib and upadacitinib (described in Chapter 4), which target only JAK1, will elucidate relevant distinctions in JAK selectivity.

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T-Cell and B-Cell Trafficking Pathway The inflammation in CD and UC is believed to be triggered by T helper (Th) 1 cells and Th2 cells, respectively.3 In CD, the increase of the cytokine IL-12 in the mucosa leads to increased Th1 response and increased IFN-γ, which, in turn, further upregulates macrophages, leading to uncontrolled inflammation.3 Tissue damage occurs when these overly activated Th1 cells and macrophages remain unregulated and activate matrix metalloproteinases.3 In UC, Th2 cells mediate B cells and antibody responses, leading to increased expression of IL-5.3 Sphingosine-1-phosphate receptor 1 (S1PR1), which is expressed on lymphocytes and endothelial cells in lymph nodes, plays an essential role in trafficking T and B lymphocytes from lymphoid organs.36,37 Activating S1PR1 induces internalization and degradation of this receptor, which renders T and B lymphocytes unable to migrate away from secondary lymphoid organs.37-39 The result is a reversible state of lymphopenia. This suggests that regulation of T-cell and B-cell trafficking has the potential to attenuate intestinal inflammation in IBD.40

Phosphodiesterase 4 Inhibition The enzyme phosphodiesterase 4 (PDE4) is considered a key player in the inflammatory cascade, because it catalyzes the breakdown of cyclic adenosine monophosphate (cAMP).41 Cyclic AMP has anti-inflammatory and immunosuppressive effects because it interferes with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. Because PDE4 controls the concentration of cAMP, inhibition of PDE4 has the potential to suppress NF-κB–dependent inflammatory conditions.41 PDE4 also mediates degradation of cAMP (a promoter of anti-inflammatory cytokines) to adenosine monophosphate (AMP; a promoter of proinflammatory cytokines).41 Thus, inhibition of PDE4 should prevent, reduce, or reverse chronic inflammation in the gut mucosa.

26

Concluding Remarks Our evolving understanding of IBD pathophysiology has led to the recognition that the gastrointestinal tract is an organ system central to immune system functioning. The interplay between the adaptive and innate immune systems is coupled with a complex interaction with the intestinal microbiota, which enables maintenance of gut homeostasis. In patients with IBD, this homeostasis has been disrupted, thus facilitating the perpetuation of unregulated intestinal inflammation. Recent advances in genetics and immunology have enabled a better understanding of IBD pathogenesis. As such, targeted therapy directed at specific dysregulated areas enables therapeutic benefit and confirmation of the underlying pathophysiology of IBD.

Key Clinical Highlights • Environmental, genetic, and microbial factors interact with the immune system, resulting in dysregulated immune responses responsible for chronic intestinal inflammation typical of CD and UC. • Discovery of the cellular and molecular mediators of intestinal inflammation has led to the development of advanced therapies, such as anti-TNF agents.

• The failure of anti-TNF therapy in a substantial proportion of patients indicates that other inflammatory pathways are likely activated in these patients.

• Other pathways implicated in IBD include the integrin-CAM pathway, JAK-STAT pathway, Interleukin signaling, PDE4 signaling, and S1P signaling.

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Thoreson R, Cullen JJ. Pathophysiology of inflammatory bowel disease: an overview. Surg Clin North Am. 2007;87(3): 575-585.

Kim DH, Cheon JH. Pathogenesis of inflammatory bowel disease and recent advances in biologic therapies. Immune Netw.

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Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018;361:k2179.

Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y, Andoh A. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol. 2018;11(1):1-10.

Nagao-Kitamoto H, Kitamoto S, Kuffa P, Kamada N. Pathogenic role of the gut microbiota in gastrointestinal diseases.

Intest Res. 2016;14(2):127-138.

Bull MJ, Plummer NT. Part 1: the human gut microbiome in health and disease. Integr Med (Encinitas). 2014;13(6):17-22.

Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol. 2015;31(1):69-75.

Dominguez-Bello MG, Blaser MJ, Ley RE, Knight R. Development of the human gastrointestinal microbiota and insights from high-throughput sequencing. Gastroenterology. 2011;140(6):1713-1719.

Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-342.

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Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38(2):127-142.

Zundler S, Becker E, Weidinger C, Siegmund B. Anti-adhesion therapies in inflammatory bowel disease-molecular and clinical aspects. Front Immunol. 2017;8:891.

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Yoshimura N, Watanabe M, Motoya S, et al; AJM300 Study Group. Safety and efficacy of AJM300, an oral antagonist of α4 integrin, in induction therapy for patients with active ulcerative colitis. Gastroenterology. 2015;149(7):1775-1783.e2.

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Lamb CA, O’Byrne S, Keir ME, Butcher EC. Gut-selective integrin-targeted therapies for inflammatory bowel disease. J Crohns Colitis. 2018;12(suppl 2):S653-S668.

Sandborn WJ, Colombel JF, Enns R, et al; International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912-1925.

Targan SR, Feagan BG, Fedorak RN, et al; International Efficacy of Natalizumab in Crohn’s Disease Response and Remission (ENCORE) Trial Group. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial.

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Amiot A, Grimaud JC, Peyrin-Biroulet L, et al; Observatory on Efficacy and of Vedolizumab in Patients With Inflammatory Bowel Disease Study Group; Groupe d’Etude Therapeutique des Affections Inflammatoires du tube Digestif. Effectiveness and safety of vedolizumab induction therapy for patients with inflammatory bowel disease. Clin Gastroenterol Hepatol.

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Bruce ES. Inhibition of interleukin-12 and/or -23 for the treatment of inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2016;12(12):784-786.

Ahern PP, Izcue A, Maloy KJ, Powrie F. The interleukin-23 axis in intestinal inflammation. Immunol Rev. 2008;226:147-159.

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Feagan BG, Sandborn WJ, D’Haens G, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet.

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Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13(4):234-243.

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Chapter 4: Targeted Mechanism-Based Therapies for IBD on the Horizon Gary R. Lichtenstein, MD Our therapeutic options for inflammatory bowel disease (IBD) have expanded greatly over the last 2 decades.

Current therapy using tumor necrosis factor (TNF) inhibitors blocks a single cytokine pathway and is able to induce complete and sustainable remission of chronic intestinal inflammation in many of our patients.

However, the failure of anti-TNF therapy in a substantial proportion of patients indicates that other inflammatory pathways are likely activated in these patients. Indeed, 10% to 30% of patients with Crohn’s disease (CD) or ulcerative colitis (UC) do not benefit from anti-TNF therapy, and as many as 50% of patients whose disease responds initially to these agents lose response over time.1 While there remains an unmet need for effective therapies, a greater understanding of the immunopathogenesis of IBD has given way to novel approaches to developing targeted therapies that are now either US Food and Drug Administration (FDA)-approved or under clinical investigation.2 VIDEO 7: What Are the Data on Fecal These advanced treatment options aim to target a Microbiota Transplantation? 
 variety of inflammatory pathways active in IBD. Gary R. Lichtenstein, MD 29

Anti-Integrin and Anti-Adhesion Molecule Agents As noted in Chapter 3, the FDA-approved anti-integrin agents include natalizumab, a monoclonal immunoglobulin (Ig) G4 antibody that binds the α4 integrin subunit, blocking both α4β7:mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) and α4β1:vascular cell adhesion molecule 1 (VCAM-1) interactions, and vedolizumab, a monoclonal IgG1 antibody that selectively targets α4β7 and blocks lymphocyte-selective trafficking to the gut by blocking α4β7:MAdCAM-1.3 Natalizumab is approved for use in CD4 and vedolizumab is approved in CD and UC5 (Table 4.1). While both drugs have been shown to be effective, natalizumab is not as widely used because it carries a risk for progressive multifocal leukoencephalopathy (PML). Several other gut-selective monoclonal antibodies have completed phase 2 trials and are currently in phase 3 trials (Table 4.2). Etrolizumab targets α4β7 and αEβ76 and abrilumab targets only α4β7.7 AJM300 is an antagonist of the α4 integrin subunit8 and PF-00547,659 (SHP647) is active against MAdCAM-1.9 There have been no reports of PML in the Phase 2 trials of these selective blockers of α4β7.

Anti-Interleukin Agents Ustekinumab is an anti-interleukin (IL) monoclonal antibody that inhibits the p40 subunit on the IL-12/23 antibody. It is FDA-approved for induction and maintenance of remission in patients who have moderately-toseverely active CD who have failed or are intolerant to a corticosteroid or immunomodulator or who have failed or are intolerant to ≥1 TNF blocker.10 Results of a phase 3 trial of ustekinumab for induction and maintenance therapy in moderate-to-severe UC demonstrated efficacy in inducing remission at 8 weeks, as well as a good safety profile.11 Brazikumab,12 risankizumab,13 guselkumab, and mirikizumab14 are other anti-IL agents in phase 2 and 3 clinical trials. These agents selectively inhibit the p19 subunit on the IL-23 antibody.

As immunosuppressants, they carry a risk for malignancy.

30

Janus Kinase Inhibitors Tofacitinib was the first Janus kinase (JAK) inhibitor to gain an FDA indication for moderately-to-severely active UC.15 Clinical trials investigating tofacitinib in CD failed to demonstrate acceptable efficacy.16 Tofacitinib 31

is known as a pan-JAK inhibitor, as it targets JAK1, JAK3, and, to a lesser extent, JAK2 and tyrosine kinase 2 (TYK2). Unlike biologic agents, JAK inhibitors are small-molecule agents administered orally and daily. The benefit-risk profile of tofacitinib appears comparable to biologic therapies. Two placebo-controlled trials demonstrated that tofacitinib induced remission in 17% and 19% of patients by week 8.17 Phase 3 safety data for the tofacitinib groups at week 8 demonstrated increased rates of infection, herpes zoster, serum low-density lipoprotein and high-density lipoprotein cholesterol, nonmelanoma skin cancer, and cardiovascular events compared with placebo.

Compared with the biologic agents, a class effect of JAK inhibitors appears to be rapid onset of action, with the potential to use the drug intermittently without generating immunogenicity. Two second-generation JAK inhibitors under investigation, filgotinib and upadacitinib, selectively target JAK1 and have shown clinical efficacy and safety in Phase 2 trials in CD.18,19 Phase 3 studies in CD and UC are underway for each agent. It is thought that JAK selectivity may be desirable to optimize efficacy and reduce undesirable effects. The offtarget effects of JAK inhibitors are classically dose dependent and are thought to occur as a consequence of the less-selective nature of these agents. Based on studies in rheumatoid arthritis and an improved understanding of JAK signaling, it has been hypothesized that specific inhibition of JAK1 may lead to a better side effect profile (eg, less neutropenia). Results of additional late-phase clinical trials will help elucidate the clinical relevance of selective JAK1 inhibition, including potential safety benefits. For example, a Phase 2 trial of an agent with TYK2 selectivity, BMS-986165, currently in Phase 2 clinical trials for CD, demonstrated efficacy in psoriasis with no neutropenia, serum creatinine elevation, dyslipidemia, or elevated liver chemistries, consistent with its selectivity for TYK2.20

Sphingosine-1-Phosphate Receptor Modulators Sphingosine-1-phosphate (S1P) receptor modulators are oral small-molecule drugs that diffuse through cell membranes more easily than the larger-molecule injectable biologics, decreasing likelihood of the development of antidrug antibodies. S1P1, S1P4, and S1P5 are involved in regulating the immune system and have been implicated in intestinal inflammation, whereas S1P2 and S1P3 are thought to be associated with cardiovascular, pulmonary, and cancer-related risks.21 Fingolimod, a nonselective oral S1P inhibitor FDAapproved for use in relapsing multiple sclerosis, inhibits S1P1, S1P3, S1P4, and S1P5. Fingolimod has not been associated with serious infection, opportunistic infections, tuberculosis, PML, or malignancy. It has, however, been associated with bradycardia, atrioventricular block, liver aminotransferase elevation, macular edema and, rarely, herpes virus infection.22 Ozanimod is under investigation as a next-generation oral S1P modulator that selectively inhibits S1P1 and S1P5 receptors, with no activity on S1P2, S1P3, and S1P4.23 Ozanimod was shown in a Phase 2 trial to be safe and effective in moderate-to-severe UC,23 and Phase 3 clinical trials for UC and CD are underway. Ozanimod has not been associated with symptomatic bradycardia or macular edema, but some minor liver function abnormalities have been seen. Etrasimod is another oral S1P modulator that selectively targets S1P1, S1P4, and S1P5, and is currently in phase 2 trials for treatment of UC.

Phosphodiesterase 4 Inhibitors Apremilast is an oral, small-molecule phosphodiesterase 4 (PDE4) inhibitor FDA-approved for the treatment of active psoriatic arthritis, and is currently under investigation for UC. A Phase 2 clinical trial of apremilast in UC demonstrated clinical remission and clinical response rates that were significantly higher compared with placebo; no safety concerns were observed.24 32

Concluding Remarks As our understanding of the pathophysiology of IBD evolves, so too does our medical therapeutic armamentarium. We recognize that the multitude of pathophysiologic perturbations that can be present in IBD means that many patients do not achieve a state of remission regardless of the agent used. As our understanding of the disease evolves, our therapies have become more targeted; as greater selectivity is realized, we may be able to achieve comparable efficacy with better safety profiles.

Key Clinical Highlights • As many as 30% of patients with IBD fail to benefit from anti-TNF therapy, and as many as 50% of patients whose disease responds initially to these agents lose response over time.

• Improved understanding of the immunopathogenesis of IBD has given way to novel approaches to developing targeted therapies that are now either FDA-approved or under clinical investigation.

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IBD Clinical Resource Center™

Guidelines ACG Clinical Guideline: Management of Crohn's Disease in Adults.

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Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

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Patient Resources Inflammatory Bowel Disease (IBD): What Is It? https://www.cdc.gov/features/inflammatory-bowel-disease/index.html

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Types of Medications for Crohn’s Disease and Ulcerative Colitis http://www.crohnscolitisfoundation.org/resources/types-of-medications.html

Treatment Decisions http://www.crohnscolitisfoundation.org/resources/treatmentdecisions.html

Advocacy Tools and Resources http://www.crohnscolitisfoundation.org/resources/advocacy-toolkits-page.html

Crohn’s Disease and Ulcerative Colitis: Emotional Factors Q & A http://www.crohnscolitisfoundation.org/resources/emotional-factors.html

The National Institute of Diabetes and Digestive and Kidney Diseases Health Information Crohn’s Disease https://www.niddk.nih.gov/health-information/digestive-diseases/crohns-disease Ulcerative Colitis https://www.niddk.nih.gov/health-information/digestive-diseases/ulcerative-colitis

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CME Posttest To receive CME credit, participants should direct their Web browsers to http://www.ExchangeCME.com/ IBDeHealth18. Participants will have two attempts to obtain a passing grade of 70% on the posttest and be eligible to obtain CME credit.

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