IBD UPDATE
From New Advances in Inflammatory Bowel Disease, sponsored by Scripps Clinic
Educational Objectives
| The goal of this program is to improve diagnosis, therapy, and long-term management of inflammatory bowel disease
(IBD). After hearing and assimilating this program, the clinician will be better able to:
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 | 1. List the stages of the endoscopic scoring system for Crohn’s disease developed by Rutgeerts et al.
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| 2. Explain the value of serologic markers and genetic variants in the diagnosis and management of IBD.
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| 3. Identify issues that confound the treatment of severe IBD.
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| 4. Develop the optimal combination of surgical and medical treatment for the IBD patient.
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| 5. Devise strategies for inducing and maintaining remission in these patients.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Binion is
on the Speakers’ Bureaus of AstraZeneca, Axcan Scandipharm, Centocor, Elan Pharmaceuticals, Procter & Gamble Pharmaceuticals,
Prometheus Laboratories, Salix Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma. He has received
grants from the National Institutes of Health and Procter & Gamble Pharmaceuticals. Dr. Rubin and the planning committee
reported nothing to disclose.
Acknowledgements
This program was recorded at New Advances in Inflammatory Bowel Disease, held April 14, 2007, in San Diego, CA,
and sponsored by the Scripps Clinic. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation
in the production of this program.
| NEWER DIAGNOSTIC AND MANAGEMENT AIDS IN IBD—David G. Binion, MD, Professor, Department of Medicine,
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee
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| Tale of 2 patients: patient 1—12-yr-old boy with weight loss and diarrhea; diagnosed with Crohn’s disease of terminal
ileum and right colon; treated with steroids and immune modifiers; patient 2—13-yr-old boy with weight loss and diarrhea;
diagnosed with Crohn’s disease of terminal ileum and right colon; treated with steroids and immune modifiers; 5 yr
later—patient 1 in clinical remission for 2 yr and growing and developing normally; repeat colonoscopies show lesions
healed; patient 2 steroid-dependent and unresponsive to most medications; underwent surgery within 6 mo of diagnosis;
puberty delayed, growth stunted; requires tube feeding, elemental diet, and total parenteral nutrition (TPN); has had
bowel perforation; has undergone third surgery for ostomy; currently doing well but hoping to get bowel reconnected in
future
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| Heterogeneity of Crohn’s disease: categories established at Vienna meeting in 1998
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| Factors involved in determining categories: onset (before or after age 40 yr); disease behavior (inflammatory, stricturing,
fistulizing); location (ileal, colonic, ileal-colonic, upper gastrointestinal [GI] tract); 24 subcategories total; patients heterogeneous
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| Evolving definition: Crohn’s disease first described in 1932 as stricturing disease of terminal ileum; colon and upper
GI tract added in 1960s; genetics—NOD2/CARD15 mutations and genetic influence identified in 2001; genetics reflects
heterogeneity; mutation seen in ≈30% of white patients but not in Asians with Crohn’s disease; also rare in
American minority groups; majority of people with mutation do not have inflammatory bowel disease (IBD); only
≈10% of people with NOD2/CARD15 mutation develop Crohn’s disease
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| Natural history: 15 yr after diagnosis, 30% of patients do not require surgery (mild disease), ≈ 33% have had one operation
(moderate), and ≈33% have undergone multiple surgeries (severe)
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| Endoscopic scoring system: devised in 1990 by Rutgeerts et al; predicts 1-yr postoperative course in patients after terminal
ileal resection; i1 lesion—mild disease (<5 small aphthous ulcers; symptomatic recurrence rare within 7-8
yr); i2 lesion—>5 aphthous ulcers, with normal mucosa in between; i3 lesion—diffuse aphthoid ileitis and extensive
inflammation; most patients experience flares; i4 lesion—severe disease, associated with diffuse inflammation
and ileal damage; 70% of patients symptomatic again within 1 yr
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| Response to therapy: mild disease—good response to mild drugs (5-aminosalicylic acid [5-ASA], budesonide); moderate
to severe disease—systemic corticosteroids indicated; immunosuppression with purine analogues and methotrexate;
patients who fail immunomodulators candidates for long-term biologic therapy (also indication for surgery)
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| Markers and subtypes of IBD: primary sclerosing cholangitis IBD—chronic cholestatic liver disease combined
with IBD; male predominance; risk for colon cancer double that associated with ordinary IBD; patients should be under
endoscopic surveillance from time of diagnosis
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| Serologic markers or genetics as predictors of IBD severity: patients may have one, several, or many markers; more
markers associated with higher risk for complications; more research needed to validate concept of markers as prognostic
predictors
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| NOD2/CARD15 C-insertion mutation: in recent study, associated with significantly increased risk for surgery among
children with newly diagnosed Crohn’s disease, compared to children without mutation
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| Impact of serologic markers on practice algorithm: in study of patients hospitalized for ulcerative colitis (UC) conducted
by speaker and colleagues, C-reactive protein (CRP) elevated in 78%; erythrocyte sedimentation rate (ESR) elevated in
≈70%; platelet count elevated in 63%; 13% of patients had no elevated markers; conclusion—routinely available
markers unreliable indicators of disease activity; similar findings obtained from first Active Ulcerative Colitis Trial
(ACT 1)
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| Health-related quality of life scores: inflammatory bowel disease questionnaire (IBDQ)—34 questions; used in large
clinical trials; short form of IBDQ (SIBDQ)—10 questions; validated; Crohn’s disease activity index (CDAI)—
valuable but hard to use in routine clinical setting (requires 7-day diary); no objective markers of inflammation; Harvey
Bradshaw index of Crohn’s disease activity—simplified index validated against CDAI; can be used clinically
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| Symptom-based therapy: symptoms assumed to coincide with disease activity (basis of phase 2 trial recruitment and clinical
care); asymptomatic patients considered “fine”; however, not all recurrences produce symptoms; Medical College
of Wisconsin study—68% of patients knew when disease active; some show disconnect between CRP levels and
SIBDQ scores; in 18%, surgical complication first symptom; 14% had symptoms but no inflammation (“IBS in IBD”)
and very poor quality of life; usually these types of patients recruited for phase 2 trials, yet they rarely feel better, and
have high rate of autonomic dysfunction
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| Rationale for treating asymptomatic disease: early detection and prevention of mucosal damage
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| MANAGEMENT OF ACUTE, SEVERE, AND/OR REFRACTORY ULCERATIVE COLITIS AND CROHN’S
DISEASE —Dr. Binion
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| Severe UC: patients may present with tachycardia, fever, weight loss, and abdominal pain; may require inpatient admission
for fulminant disease; ≈10% of UC patients require surgery at beginning of disease process
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| Confounding issues associated with severe IBD
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| Clostridium difficile—anaerobic spore-forming bacillus associated with pseudomembranous colitis; incidence has doubled
in North America over past 5 yr; metronidazole failure rate ≈50%; IBD patients represent growing proportion of
all patients with C difficile infection; spores may persist outside body for 60 to 70 days; not killed by alcohol-based
hand rubs; washing with soap and water essential to remove spores from hands and prevent transmission; IBD risk factor
for C difficile infection; patients often require hospitalization and colectomy; body must mount humoral immune
response to fight infection; however, IBD patients often treated with high-dose steroids, which block antibody response;
steroids contraindicated when C difficile infection suspected; does not form classic pseudomembranes in patients
with IBD; in recent study at Medical College of Wisconsin, 40% of infected IBD patients had no history of
recent antibiotic use (antibiotics in food supply suspected); C difficile now found in cows and pigs; suspicion that IBD
patients more susceptible to C difficile; risk also correlated with maintenance immunosuppression (purine analogues,
methotrexate); contributes to flare in new and longstanding cases in remission; multiple stool assays essential for diagnosis;
if response to metronidazole not prompt, consider vancomycin (only Food and Drug Administration [FDA]-approved
drug for fighting C difficile)
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| Hypersensitivity reactions to standard IBD drugs: 5-ASA hypersensitivity occurs in ≈4% of IBD patients; symptoms include
bloody diarrhea and abdominal pain; partially treated with steroids; diagnose by discontinuing 5-ASA (inappropriate
anyway for hospitalized patients; indicated only for mild to moderate disease); drugs sometimes make patients
feel worse, leading to nonadherence; estimated that as many as 34% of patients may be intolerant to purine analogues;
usually manifested as nausea and abdominal pain, but subgroup may develop severe reactions (eg, pancreatitis, bronchiolitis
obliterans); usually begins ≤1 mo after starting drugs; partially treated with steroids
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| Treating severe UC: infliximab—50% to 66% of patients responded in ACT 1 and 2 trials; also shows promise in inpatient
setting; cyclosporine—2-mg/kg infusion recommended; infection possible complication; surgery—indications
include hemorrhage, frank perforation, suspicion of cancer, lack of response to drugs, and steroid dependence
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| Treating severe Crohn’s disease: includes patients with severe, acute, or refractory disease, small bowel obstruction,
severe duodenal disease with gastric outlet obstruction, fulminant Crohn’s colitis, high risk for surgical recurrence, and
severe postsurgical complications; treatment involves close collaboration with surgeon; consider maintenance immunosuppression
and biologic therapy; over 20 to 30 yr, ≈80% of patients need surgery
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| Optimal combination of medicine and surgery: diagnostic plan—search for occult strictures (may be difficult to find; often
missed on x-ray; more detected with intraoperative balloon); web strictures also occur and easily missed, even
during surgery
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| Perioperative issues: nutrition—patients often have gut failure or strictures; TPN helps boost albumin level and lower
surgical risk; vitamin B12 deficiency common; anticoagulation—hypercoagulability common, due to inflammation,
elevated platelet counts, vitamin B12 deficiency, and dehydration; 90% of patients have had clotting event; low-molecular-weight
heparin recommended for inpatients and surgical patients; pain management—avoid nonsteroidal
anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 inhibitors; NSAIDs promote vascular constriction,
which contributes to mucosal deterioration and ulceration
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| Short-term issues: safety of immunomodulators and biologic agents at time of surgery; in study of 100 surgical patients,
speaker and colleagues found that 72 on immunomodulators; 4 of those (5.6%) experienced septic complications,
compared to 7 of 28 patients (25%) not on immunomodulators; conclusion—medical control at time of surgery
associated with lower risk for sepsis
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| Postoperative issues: speaker and colleagues found that 7% of patients require reoperation within 2 yr; of those, about
two-thirds not on maintenance medical therapy
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| Refractory disease: drug choices include antibiotics, steroid compounds, elemental diet, TPN, and immunosuppressive
and biologic agents; refer patients to large IBD centers
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| MAINTAINING REMISSION IN IBD, INCLUDING POSTSURGICAL MANAGEMENT —David T. Rubin, MD, Associate
Professor, Department of Medicine, Section of Gastroenterology, and Program Director, Fellowship in Gastroenterology,
University of Chicago Pritzker School of Medicine, Chicago, IL
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| Maintenance of remission in IBD: strategies to prevent relapse or postoperative recurrence; remission must be successfully
induced first; patient should be steroid-free; does not mean suppression of active symptoms, short-term stable
remission, or long-term steroid use; emphasize to patient that goal of maintenance therapy to lower risk for relapse and
complications over longer term
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| Potential benefits of successful maintenance strategies: hard data scarce, but benefits should include lower direct
and indirect costs of care; more durable response to therapies; less need for therapy escalation (“dose creep”); reduced
risk for complications; reduced need for surgery; reduced risk for cancer
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| Maintenance of remission in UC: induce remission with 5-ASA; encourage adherence to therapy; reports of renal
dysfunction, so periodically assess renal function (creatinine, urinalysis); limited data suggest against reducing dose after
remission achieved, although “that’s far from conclusive”; some evidence associates 5-ASA use with reduced cancer
risk (also not conclusive); compared to 5-ASA, azathioprine (AZA) yields superior results in steroid-dependent
patients (place on AZA as early as possible); AZA or 6-mercaptopurine (6-MP) may be steroid-sparing; among patients
on cyclosporine, adding AZA or 6-MP to follow-up regimen increases chances of maintaining remission; patients
who fail AZA and 6-MP therapy usually not considered candidates for cyclosporine, due to lack of maintenance
exit strategy; infliximab—maintains remission for only 30 wk; questions remain over when to use it; cancer risk—
associated with severity of histologic inflammation; successful maintenance minimizes inflammation over time, possibly
reducing long-term risk for cancer and dysplasia
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| Adherence to therapy: essential for maintaining remission; however, often problematic; predicted by factors including disease
activity, and whether patient newly diagnosed or new to physician’s practice; patient-related factors—financial need (ask
patient how they plan to pay for medication); inadequate education about disease or treatment (may not understand concept
of maintenance); lack of personal support system; perception that medicine unnecessary when disease quiescent; strategies
for promoting adherence—individualize therapy; minimize side effects; provide reminders to patients about when to take
medication; schedule more frequent office visits for patients more likely to be nonadherent; prescribe for longer intervals to
minimize pharmacy visits; tailor regimen to patient’s lifestyle; simplify regimen as much as possible
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| Maintenance of remission in Crohn’s disease: steroids should not be used for long-term management; budesonide
approved as maintenance therapy for disease of ileum and proximal colon, based on pooled analysis showing
longer time to relapse with 6-mg dose; supports use of drug in repeated cycles of therapy for rare patients;
AZA—maintains remission in adults and children; most patients require long-term therapy; methotrexate—
superior to placebo for maintaining remission; natalizumab—shown to provide stable maintenance in people
with Crohn’s disease over 24 mo
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| Recurrence: still poorly understood; effect of antibiotics not durable; quitting smoking most important thing patients can
do postoperatively to reduce risk for recurrence; postoperative metronidazole associated with relatively short-lived
benefits and significant side effects; questionable data suggest AZA may be superior to 5-ASA in preventing recurrence;
large well-designed study now under way
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| Speaker’s approach to postoperative prevention: tailor strategies to individual patients (eg, more aggressive therapies for
more severe cases who have undergone repeat surgeries within 2 yr; perhaps no treatment at all for patient with 10-yr
stricture who finally undergoes surgery)
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Suggested Reading
Ananthakrishan AN et al: Excess hospitalization burden associated with Clostridium difficile in patients with inflammatory
bowel disease. Gut 57:205, 2008; Binion DG et al: Clinical factors contributing to rapid reoperation for Crohn’s
disease patients undergoing resection and/or strictureplasty. J Gastrointest Surg 11:1692, 2007; Bruining DH, Loftus
EV Jr: Evolving diagnostic strategies for inflammatory bowel disease. Curr Gastroenterol Rep 8:478, 2006; Daperno M
et al: The role of endoscopy in inflammatory bowel disease. Eur Rev Med Pharmacol Sci 8:209, 2004; Issa M et al: Impact
of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol 5:345, 2007; Loftus EV Jr: Biologic
therapy in Crohn’s disease: review of the evidence. Rev Gastroenterol Disord 7 Suppl 1:S3, 2007; Rodriguez-
Bores L et al: Novel genetic markers in inflammatory bowel disease. World J Gastroenterol 13:5560, 2007; Rubin DT
et al: Colorectal cancer prevention in inflammatory bowel disease and the role of 5-aminosalicylic acid: a clinical review
and update. Inflamm Bowel Dis 14:265, 2008; Rubin DT, Kornbluth A: Role of antibiotics in the management of inflammatory
bowel disease: a review. Rev Gastroenterol Disord 5 Suppl 3:S10, 2005; Rutgeerts P et al: Predictability of
the postoperative course of Crohn’s disease. Gastroenterology 99:956, 1990; Van Limbergen J et al: The genetics of
inflammatory bowel disease. Am J Gastroenterol 102:2820, 2007; Wang YF et al: Clinical manifestations of inflammatory
bowel disease: East and West differences. J Dig Dis 8:121, 2007.
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