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

2. 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 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

3. 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

4. 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.

5. 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

6. 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 children with IBD
100,000 cases diagnosed annually in North America

7. 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

8. 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.

9. 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.

10. 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.

11. 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.

12. 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

13. 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

14. 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

15. 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.

16. 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

17. 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

18. 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

19. 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

20. 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.

21. 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

22. 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)

23. 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

24. 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)

25. 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

26. 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

27. 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

28. 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.

29. 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

30. 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

31. 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