Inflammatory Bowel Disease Samantha Fish, MD Andrew Grossman, MD Children’s Hospital of Philadelphia Reviewed by Edward Hoffenberg, MD of the Professional Education Committee

Case Presentation 13yo female presents with 2mo history of abdominal pain, diarrhea with intermittent blood and 10lb weight loss Examination reveals soft abdomen with fullness appreciated in the RLQ, pain on palpation of RLQ, otherwise normal exam Laboratory evaluation reveals WBC 7, Hgb 11, Plt 517, Alb 3.1, ESR 50, CRP 3.2. Remainder of CBC and CMP normal Can discuss what the next steps would be. Stool studies to rule out infection, especially c. diff Endoscopy and colonoscopy to evaluate for inflammatory bowel disease Small bowel imaging to look for small bowel inflammation

Background: Inflammatory Bowel Disease Chronic inflammatory disease of the intestinal tract Usually characterized by progressive damage to the gastrointestinal tract Pediatrics: risk for complications in growth, malnutrition, bone disease, psychosocial issues Pathogenesis poorly defined IBD is being identified more frequently in the US

Etiologic Theories in Inflammatory Bowel Disease Genetic Predisposition Mucosal Immune System (Innate/Adaptive) IBD Environmental Triggers (Luminal Bacteria, Infection) Current theories on the etiology of inflammatory bowel disease: Currently thought to occur in a patient with a genetic predisposition who encounters some unknown environmental trigger which turns on the GI tract immune system. This then leads to over production of inflammation and inflammatory cytokines that inappropriately respond to our own GI tract microbiome. At this time there are 163 known genes that increase risk of development of IBD. Triggers may include infection, use of antibiotics, changes in microbiome. Studies have shown that the microbiome in patients with IBD is often altered from that of healthy controls with different bacterial populations present. Somehow the interaction of all these things leads to the uncontrolled inflammation seen in patients with IBD. Clinical and basic research in inflammatory bowel disease has suggested that three factors are critically important in the development of inflammatory bowel disease in the a given individual. First, patients inherit genes that predispose to inflammatory bowel disease. These genes may result in abnormalities in the mucosal immune system such as overproduction of pro-inflammatory cytokines or under-production of anti-inflammatory or regulatory cytokines. Finally, a triggering event must occur to set in motion the chronic inflammation. This triggering event is generally believed to be bacteria but may include other environmental factors such as smoking or NSAIDS.

IBD in Pediatric Patients Similarities with adults Disease and therapy are generally the same Differential diagnosis is commonly similar for patients over the age of 5 years Differences with adults Lack of specific pediatric data Lack of child-appropriate formulations Unique growth and development problems Patients diagnosed with IBD under the age of 5 should also be screened for immune deficiency as this can be an underlying cause of IBD in very young patients

How Common is Pediatric IBD in U.S.? Incidence increasing among children 2004: ~ 1.4 million Americans with IBD Pediatric Incidence in USA: CD: 4.5/100,000 UC: 2/100,000 Pediatric Prevalence: 45,000-100,000 children with IBD 100,000 cases diagnosed annually in North America

20-25% of IBD cases diagnosed by 20 years Age of Onset of IBD Years 10 20 30 40 50 60 70 80 25 20 Percent of Cases 15 10 Because high rates of IBD onset occur in childhood and adolescence (peak incidence between 15 to 25 years of age), monitoring the incidence of pediatric IBD may reflect changing trends in IBD demographics. Recent retrospective European studies and one prospective population-based survey from the UK have suggested that the incidence of IBD in children and adolescents has significantly increased over the last 35 years. In addition, data from European pediatric studies also suggest that there has been a change in the patterns of disease, as the incidence of CD has risen above that of UC. Loftus EV, Gastroenterology. 2003 5 20-25% of IBD cases diagnosed by 20 years Loftus, Gastroenterology 2003, abstract

Crohn’s Disease vs. Ulcerative Colitis Any part of the GI tract Discontinuous Rectal sparing Ileum commonly involved Perianal disease Transmural inflammation Fistulae and abscesses Granulomas Strictures common Ulcerative Colitis Colon only (+/- gastritis Continuous No rectal sparing +/- backwash ileitis No perianal disease Mucosal inflammation Abscesses very rare No granulomas Strictures rare The definitive diagnosis of IBD is established by a combination of radiography, endoscopy, and histology. Differentiating Crohn’s disease from ulcerative colitis can be difficult, especially if the IBD is limited to the colon. The diagnosis of Crohn’s disease can be made definitively if there is clear small bowel inflammation (not simply “backwash ileitis”), discontinuous colitis, perianal disease, or granulomas identified on biopsy. Over time, the natural history of the two diseases differs. Patients with Crohn’s disease will frequently develop complications such as strictures, abdominal abscesses, or perianal fistulae, whereas patients with ulceratie colits continue to have bloody diarrhea as their principal manifestation.

IBD Presentation Symptoms/Signs CD UC Rectal bleeding ++ ++++ Diarrhea ++ ++++ Weight loss ++++ ++ Growth failure ++++ + Perianal disease ++ - Abdominal pain ++++ +++ Anemia +++ +++ Mouth ulcers ++ + Fevers/Arthritis ++ + IBD involving the colon (whether ulcerative colitis or Crohn’s disease) most commonly presents with diarrhea and rectal bleeding. In contrast, Crohn’s disease involving the terminal ileum and/or cecum tends to present more subtly, with abdominal pain, weight loss, fatigue, and fever. Perianal fistulae and infections are seen in Crohn’s disease, but not ulcerative colitis. Extraintestinal manifestations (e.g. erythma nodosum, arthritis) are seen in both CD and UC, but are a presenting feature less than 15% of the time.

Initial Laboratory Evaluation Complete blood count and differential Anemia, thrombocytosis common ESR, CRP Typically elevated with active inflammation Comprehensive metabolic panel Screen for liver abnormalities Hypoalbuminemia  Highly suggestive Rule out enteric infection, celiac disease IBD Serology: promising, but not proven If IBD is suspected, laboratory tests may provide additional clues to the diagnosis. This may include complete blood count (which might show anemia and thrombocytosis), acute phase reactants such as the eythrocyte sedimentation rate and C-reactive protein, transaminases, and albumin level. Serologic testing is usually not necessary to establish the diagnosis when clinical signs are obvious, but it may be useful in more subtle cases. Laboratory test may be completely normal, especially in mild disease such as proctitis.

Radiology Testing Traditional Modalities Recent trends Upper GI with Small Bowel Follow-Through Barium Enema CT scan Recent trends High resolution ultrasound MRI pelvis/abdomen CT enterography Radiology testing allows visualization of the small bowel which can not be seen with endoscopy and colonoscopy. It is important to obtain small bowel imaging with diagnosis of IBD to evaluate extent of disease and to be able to follow this over time. Crohn’s of the terminal ileum is often first identified on upper GI with small bowel radiograph, which shows ileal stenosis and separation of bowel loops. Radiology testing can also be helpful in distinguishing UC from Crohn’s if there is colitis alone on colonoscopy.

Endoscopy/Colonoscopy Crohn’s disease Crohn’s disease often shows a patch colitis with skip lesions and apthous ulcerations. Ileitis can also be assessed endoscopically and in Crohn’s disease can demonstrate stenosis, linear ulceration, and mucopurulent exudate. Patchy Colitis Crohn’s ileitis Aphthous Ulcerations

Endoscopy/Colonoscopy Ulcerative Colitis Ulcerative colitis often starts at the rectum and inflammation works its way proximally. There can be an abrupt transition zone of abnormal to normal mucosa as seen in the first picture. UC can also present as a confluent, pancolitis as seen in the second picture. Pancolitis Colitis with Transition Zone

Colitis with Granuloma Histopathology Colitis Crypt branching, distortion Crypt abscess Hypercellular Histopathology in IBD often shows increase inflammatory cells within the lamina propria showing chronic inflammation and crypt abscesses with branching of crypts. Presence of granulomas in the face of chronic inflammation is consistent with a diagnosis of Crohn’s disease. Colitis with Granuloma

Capsule Endoscopy Relatively easy to swallow Endoscopically placed in younger patients Can visualize entire small bowel MUST rule out intestinal stricture prior to placement Capsule endoscopy allows visualization of the small bowel without the ability to take biopsy samples.

Treatment of Pediatric IBDGoals Improve growth and nutrition Improve quality of life Maximize therapeutic response Minimize toxicity Prevent disease complications Maximize adherence Promote psychological health

Pediatric IBD “Step-Up” Algorithm Severe Surgery Biologic therapy Moderate Prednisone 6-MP Imuran Methotrexate Enteral Nutrition Steroids Traditional thinking for IBD treatment Budesonide Mild Antibiotics (Probiotics) Aminosalicylates

Pentasa® (mesalamine) Aminosalicylates Asacol® (mesalamine) Pentasa® (mesalamine) pH released 5-ASA Time released 5-ASA Dipentum® (olsalazine) Azulfidine® (sulfasalazine) Colazal® (balsalazide) 5-ASA + 5-ASA 5-ASA + Sulfapyridine 5-ASA + inert carrier

Aminosalicylates (5-ASA) Locally reduce inflammation in the bowel Inhibition of arachidonic metabolism Oral and rectal preparations available Often a first-line therapy for UC and Crohn’s Role in decreasing risk of colon cancer Well tolerated Headaches, GI complaints most common 3-5% with allergy to medicine Adherence can be an issue with large number of pills to be taken multiple times daily

COLAZAL/AZULFIDINE/DIPENTUM 5-ASA Delivery Systems PENTASA ASACOL ENEMA SUPP COLAZAL/AZULFIDINE/DIPENTUM JEJUNUM / ILEUM / ASCENDING / DESCENDING / SIGMOID / RECTUM SMALL BOWEL COLON This slide graphically shows the site of release of the active drug for the various forms of aminosalicylates that are commercially available in the United States. Note that while all cover the colon, only the mesalamine preparations offer true drug release in the small intestine, which is a frequent site of activity in Crohn’s disease.

Efficacy of 5-ASA’s Ulcerative Colitis Oral and rectal forms Oral therapy effective for induction and maintenance of remission Rectal + oral  More effective than just oral for distal disease Crohn’s disease Efficacy unclear for induction or maintenance of remission

Antibiotics Flagyl (metronidazole) Decrease inflammation by changing or eliminating bacteria in GI tract Multiple indications for Crohn’s Perianal disease Abscess Prevent post-operative recurrence Treatment of mild or moderate disease Not proven effective for UC Cipro (ciprofloxacin)

Systemic Corticosteroids Oral (prednisone), IV (Solumedrol), or rectal Suppress active inflammation Indication: Crohn’s flare Provide immediate symptomatic relief Do not promote GI tract mucosal healing Not indicated for maintenance therapy

Entocort (Budesonide) Rapid hepatic clearance formulation Released in the terminal ileum Considerably less steroid side effects Effective for ileocolonic Crohn’s disease Not effective for UC, Crohn’s colitis or gastritis Role as maintenance therapy unclear Evidence of some steroid side effects (growth suppression)

Enteral Nutritional Therapy Improves nutrition for all IBD Effective therapy for pediatric Crohn’s 100% of calories by formula 80-90% as effective? Usually requires NG tube As effective as steroids for improving symptoms, more effective for healing of GI inflammation Likely mechanism  Change in intestinal microflora

Immunomodulators Suppress immune response that triggers intestinal damage in IBD Induction and maintenance of remission Steroid-sparing 6-MP/Imuran Daily dosing Oral administration 3-4 months for max. efficacy Methotrexate Once weekly dosing Oral or subcutaneous 6-8 weeks for max. efficacy

Biologic Therapies Remicade Pro-inflammatory cytokines contribute to inflammation in IBD TNFα is elevated in IBD patients Biologics block and neutralize cytokines Used to treat moderate to severe IBD not responding to other therapy Infusion (Infliximab = Remicade) Injectable (Adalimumab = Humira) (infliximab) 75% Human Humira Remicade’s structure is 80% human and 20% mouse. Antibiodies are produces against the mouse piece of the antibody. Humira’s structure is 100% humanized. (adalimumab) 100% Human

Biologics Pre-screening for TB prior to initiation of therapy Infliximab Infusion over 2 hours Loading dose of 0, 2, and 6 weeks Maintenance dose every 8 weeks Adalimumab Injection Maintenance dose every 2 weeks Side Effect Profile Infection, malignancy, infusion reaction, serum sickness, psoriasis Possible side effects and adverse outcomes with remicade: Formation of antibodies, Infusion reactions, anaphylaxis, Hypersensitivity reactions Increased risk of infections, Tuberculosis activation, Increased risk of lymphoma (rare). Live vaccine should not be administered to patients on Remicade due to the concern for re-activation of virus in immunosuppressed patient.

Humira (adalimumab) Humanized antibody to TNFα Subcutaneous injection every two weeks Requires loading dose Similar efficacy as Remicade? Similar adverse effects ↓ risk of antibody formation

Future Directions  Does Early Use of Biological Therapy Improve Efficacy? Growth? Biologic therapy Early 6-MP/AZA/Methotrexate Steroids 5-ASA Antibiotics Question on whether early introduction of biologic therapy will have better outcomes in patients with moderate to severe Crohn’s disease. Possible avoidance of surgery, decreased complications over time, improved growth? Surgery Late 5-ASA, antibiotics

Case Conclusion Colonoscopy showed gross pancolitis confirmed by histology Patient started on oral and rectal 5-ASA as well as an immunomodulator with symptom improvement