Inflammatory Bowel Disease

1
Inflammatory Bowel Disease
2
Definition

• Inflammatory bowel disease (IBD) is a term
  encompassing a number of chronic inflammatory
  disorders leading to damage of the
  gastrointestinal tract.

3
Crohns disease
4
Symptoms of CD

• The presentation depends on the site, extent,
  severity, and complications of intestinal and
  extraintestinal disease.
• Fevers, night sweats, and weight loss.
• Abdominal pain
• Nausea and vomiting
• Diarrhea
• Rectal bleeding

5
Extraintestinal Manifestations of Inflammatory
Bowel Disease

• Musculoskeletal
• Peripheral arthritis
• Sacroiliitis
• Ankylosing spondylitis
• Osteoporosis
• Dermatologic
• Erythema nodosum
• Pyoderma gangrenosum
• Aphthous stomatitis
• Hepatobiliary Disease
• Primary sclerosing cholangitis

• Ocular
• Uveitis
• Scleritis
• Episcleritis
• Vascular
• Thromboembolic events
• Renal
• Nephrolithiasis

6
Physical Examination in CD

• Weight loss and pallor.
• Clubbing of the fingers.
• Abdominal distension
• Tenderness in the area of involvement
• Abnormal bowel sounds.
• Presence of an inflammatory mass are common.
• Perianal abscess, fistula, skin tags, or anal
  stricture.

7
Laboratory Studies

• Anemia
• Deficiencies of iron, vitamin B12, or folic acid
• Anemia of chronic disease.
• Leukocytosis
• Thrombocytosis
• Elevated ESR and C-reactive protein levels
• Decreased Serum albumin levels
• Urinalysis commonly demonstrates calcium oxalate
  crystals.
• Stoolanalysis for fecal leukocytes
• Serologic markers with high specificity for CD.
• Anti-Saccharomyces cerevisiae antibody(ASCA)
• Antibody to the outer core membrane of E. coli
  (OmpC)

8
Imaging Studies

• Plain abdominal x- ray
• Barium studies
• Small bowel enema (enteroclysis) /
  follow-through
• Large bowel enema
• U/S Abdomen and Pelvis / Transrectal U/S
• CT Abdomen and Pelvis
• MRI

9
CD
Typical features of Crohn's disease of the distal
ileum including fissure ulcers (small arrows),
longitudinal ulcers (arrowhead), "cobblestoning"
(open arrows), aphthoid ulcers (curved arrow) and
stricturing. icileocaecal valve.
Aphthoid ulceration of terminal ileum (small
arrows)- Note also "cobblestoning" (larger
arrows).
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Endoscopy

• Upper and Lower Endoscopy
• Capsule Endoscopy

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CD
12
CD
13
CD
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Granuloma in CD
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ACG Practice GuidelinesDefinitions of Disease
Severity
Mild Moderate CD

• Ambulatory patients
• Patients who are able to tolerate oral
  alimentation
• Patients without manifestations of
• Dehydration
• Toxicity ( high fever, rigors, prostration )
• Abdominal tenderness
• Painful mass
• Obstruction
• gt10 weight loss

Hanauer et al A J Gastroenterology 2001,96,635
16
ACG Practice GuidelinesDefinitions of Disease
Severity (cont.)
Moderate-Severe CD

• Patients who have failed to respond to treatment
  for mild-moderate disease
• Patients with more prominent symptom of
• Fever
• Significant weight loss
• Abdominal pain or tenderness
• Intermittent nausea or vomiting (without
  obstructive findings)
• Significant anemia

Hanauer et al A J Gastroenterology 2001,96,635
17
ACG Practice GuidelinesDefinitions of Disease
Severity (cont.)
Sever Fulminant CD

• Patients with persistent symptoms despite the
  introduction of steroids as out patient
• Individuals presenting with
• High fever
• Persistent vomiting
• Evidence of intestinal obstruction
• Rebound tenterness
• Cachexia, or
• Evidence of abscess

Hanauer et al A J Gastroenterology 2001,96,635
18
ACG Practice GuidelinesDefinitions of Disease
activity
CD in remission

• Patients who are asymptomatic or without
  inflammatory sequelae
• Patients who have responded to acute medical
  intervention or have udergone surgical resection
  without gross evidence of residual disease
• NB Patients requiring steroids to maintain
  well-being are considered to be
  steroid-dependenand are usually not cosidered
  to be in remission.

Hanauer et al A J Gastroenterology 2001,96,635
19
Long-term disease evolution behavior in CD
Cosnes J et al. Inflamm Bowel Dis 20028244
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Medical treatment of IBD

• Yousef A. Qari MD,FRCPC,ABIM
• Consultant Gastroenterologist
• King Abdulaziz University Hospital
• Jeddah, Saudi Arabia

21
Current Expectations for IBD Therapy

• Induce clinical remission
• Maintain clinical remission
• Improve quality of life
• Plus
• Heal mucosa
• Decrease hospitalization / surgery / overall
  costs
• Minimize disease- related and therapy-related
  complications

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ACG Practice GuidelinesRecommended treatment
Mild Moderate CD
Remission

• Aminosalicylates
• Sulphasalazine (3-6g/d)
• Mesalamine (3.2-4.0g/d)
  40-50
• Antibiotics (CD involving colon)
• Metronidasole (10-20mg/kg)
  50
• Ciprofloxacin (1g/d)
• MetroCipro (250mg 2-3 times/d 500mg 2 times/d)
  76
• Budesonide (CIR) (9mg/d)
• For ileal Rt colonic disease
  69

23
ACG Practice GuidelinesRecommended treatment
Moderate Severe CD

• Corticosteroids
• Appropriate antibiotics therapy or drainage
  (surgical/percutaneous) required for infection or
  abscess
• Inflximab infusion
• Effective adjunct
• Possible alternative to steroid therapy in
  selected patients in whom corticosteroids are
  contraindicated or ineffective.

24
Oral Budesonide for active CD
Greenberg etal . N Engl J Med 1994331836-41
25
ACG Practice GuidelinesRecommended treatment
Moderate Severe CD

• Corticosteroids
• Budesonide 9mg/d or
• Prednisone (0.5-0.75mg/kg) or 40mg/d
• 5o-70 remission rate in 8-12 weeks
• Until resolution of symptoms and resumption of
  weight gain, generally 7-28 days.
• Steroid refractory steroid dependent 50
• Smooking
• Colonic disease
• Not effective for maintenance
• 
  

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Clinical response and remission in
Infliximab-treated patients
Moderate-Severe CD
Clinical response 70 points decrease in CDAI
from baseline Clinical remission a CDAI of lt 150
Targan SR et al, N Engl J Med. 19973371029
27
Clinical Response at Week 52
Plt0.001
PNS
Plt0.001
Week-2 Responders
28
Clinical Remission at Week 54
Plt0.001
PNS
Plt0.007
Week-2 Responders
29
ACG Practice GuidelinesRecommended treatment
Severe-Fulminant CD

• Hospitalization required for
• patients with persistent symptoms despite
  introduction of oral steroids or infliximab
• Patients presenting with high fever, frequent
  vomiting, evidence of intestinal obstruction,
  rebound tenderness, cachexia, or an abscess
• Surgical consultation is warranted for
  patients with obstruction or tender abdominal
  mass.

Hanaur S et al. Am J Gastroenterology 96 635
30
ACG Practice GuidelinesRecommended treatment
Severe-Fulminant CD

• Exclude abscess
• Abd US
• Abd CT
• Parentral corticosteroids equivalent to 40-60mg
  prednisone
• If abscess has been excluded
• If the patient has been receiving oral setroids

Percutaneous
Drainage
Surgical
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ACG Practice GuidelinesRecommended treatment
Severe-Fulminant CD

• Parentral broad spectrum antibiotics
• High fever
• Toxic appearance
• Inflammatory mass
• Nutritional support (Elemental or TPN)
• TPN in addition to steroids plays no specific
  role
• Indications
• For patients unable to maintain nutritional
  requirments after 5-7 days
• Preoperative management
• Pediatric age groups

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Therapeutic Options for Perianal Fistulas in CD

• Possible efficacy
• Antibiotics
• AZT/6-MP
  
• Cyclosporine

• Proven efficacy
• Infliximab

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Therapeutic Options for Perianal Fistulas in CD
AZT/6-MP
22/41
Compleate healing or decreased discharge?
Pearson DC et al. Ann Intern Med.1995122132
34
Therapeutic Options for Perianal Fistulas in CD
Infliximab
P0.001
P0.04
Present DH et al. N Engl J Med. 1999341398
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Step-up versus Top-down Trial
Newly Diagnosed Crohn (N 129)
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Step Up treatment paradigm driven by cost, safety
and adverse events
Surgery
Infliximab Immunosuppressives
Steroids Elemental diet Antibiotics
Aminosalicylates
The classical Step-Up-treatment paradigm
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Azathioprine is the best conventional drug to
maintain clinical remission
Remission induced by prednisolone tapered over
12 wk
100
ster AZA
AZA
0
15
Candy S et al. Gut. 199537674.
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Continuous Immunotherapy is required to treat a
Chronic Disease
Patients in clinical remission with AZA for at
least 3.5 years before randomisation
Months after randomisation
Lemann et al. Gastroenterol. 2005
Jun128(7)1812-8.
41
Cumulative Probability of Surgical Intervention
in CD
100
80
60
Probability ()
40
20
0
0
2
5
8
11
14
17
20
Dx
Years
Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1
Munkholm P et al. Gastroenterology. 1993
1051716.
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Ulcerative colitis
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Difinition

• A chronic disease charecterized by diffuse
  mucosal inflammation limited to the colon.

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Age distribution of Ulcerative colitis in east
and west provinces of Saudi arabia 188 CASES
Age(y) at presentation

• Qari Y et al, under publication
• 2. Satti M et al, Ann Saudi Med
  199616(6)637-640.

45
Sex distribution of UC in the Gulf

1. Qari Y et al, under publication
2. Hossain J et al. Ann Saudi Med 19911140-6.
3. Satti M et al, Ann Saudi Med 199616(6)637-640.

4. Al-Nakib B et al. Am J Gastroenterology
198479191-4 5. Mir-Madjlessi SH et al. Am
J Gastroenterology 198511862-6.
46
Pattern of UC in the Gulf

• Qari Y et al, under publication
• Hossain J et al. Ann Saudi Med 19911140-6.
• Satti M et al, Ann Saudi Med 199616(6)637-640.
• .

4. Al-Nakib B et al. Am J Gastroenterology
198479191-4 5. Mir-Madjlessi SH et al.
Am J Gastroenterology 198511862-6.
47
Epidemiological figures comparing East vs West
Geographic location Gulf Region Saudi Arabia West Europe and USA
Incidence 0.5 2.8 / 100 000 6 -8 / 100 000
Prevalence 5 / 100 000 70 -150 /100 000
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Ulcerative colitis
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UC Normal
50
UC
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UC
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The goals for the management of acute ulcerative
colitis

• Induction of remission
• Prevention of relapse
• Treatment of complications

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Therapeutic decisions
Disease Activity ??
Extent of Disease ??
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Disease Activity

• Mild
• Moderate
• Severe
• Fulminant

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Mayo score
Schroeder KW et al. N Engl J Med 1987 317
1625-9.
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Mayo score
Schroeder KW et al. N Engl J Med 1987 317
1625-9.
57
Mayo score
Schroeder KW et al. N Engl J Med 1987 317
1625-9.
58
Mayo score
Schroeder KW et al. N Engl J Med 1987 317
1625-9.
59
Endoscopy Photo Sample Scores
Endoscopy score 0
Endoscopy score 1
Endoscopy score 3
Endoscopy score 2
60
Mayo score
Schroeder KW et al. N Engl J Med 1987 317
1625-9.
61
Mayo score
Schroeder KW et al. N Engl J Med 1987 317
1625-9.
62
Severe colitis

• A bloody stool frequency of gt 6/day with any
  one of the following
• Tachycardia (pulse gt 90 beats/min)
• Temperature (gt 37.8 C)
• Anaemia (Hg lt 10.5 g/dL)
• Raised ESR (gt 30 mm/h)

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Extent of Disease
64
Medical Therapy
Activity
Extent
65
Superiority of topical 5-ASA to placebo in
treatment of mild to moderate Distal UC.
Seven RCTs
66
Superiority of topical 5-ASA to placebo in
treatment of mild to moderate Distal UC.
67
5-aminosalicylic acid preparations (all study
arms) compared with placebo in active ulcerative
colitis.
Adapted from Sutherland et al. Ann Intern Med
1993 118 5409.
68
Combined oral and topical treatment with 5-ASA
in active extensive UC, proximal to the splenic
flexure.
P 0.03
(NS)
Marteau P et al. Gut 2005 54 9605.
69
Topical 5-ASA have superior efficacy to oral
mesalazine in the maintenance of remission in
Distal Colitis
Mantzaris GJ et al. Dis Colon Rectum 1994 37
5862.
70
RCTs of mesalazine vs. placebo for preventing
relapse in patients with UC
27. Ardizzone S et al.Aliment Pharmacol Ther
1999 13 3739. 23. Hanauer S et al .Ann Intern
Med 1996 124 20411. 25. Hawkey CJ et al.
Gastroenterology 1997 112 71824. 24. Miner P
et al. Dig Dis Sci 1995 40 296304.
71
The New Aminosalicylates for UC

• Equivalent to sulfasalazine
• Inducing remission
• Maintaining remission
• Fewer side effects

72
Compliance is a problem
73
Patient Non-compliance with 5-ASA Treatment
Regimens
Kane SV et al. Am J Gastroenterol 2001 96
2929-33.
74
Clinical Impact of Non-adherence to therapy for UC
Greater risk of symptomatic relapse
(P 0.001)
Kane S. Am J Med 2003 114 39-43.
75
Clinical Impact of Non-adherence to therapy for UC
Greater risk of colorectal cancer
175 patients
The lifetime risk of colorectal cancer among
patients with UC is estimated to be approximately
20
(P lt 0.001)
Brentnall TA. Curr Opin Gastroenterol 2003 19
64-8.
76
Mesalazine 2 g gel enema is as effective as and
more convenient than mesalazine 2 g foam enema
Plt0.005
Plt0.05
103 patients
4 weeks
Plt0.05
Remission rates were comparable between the two
groups.
Gionchetti P. Aliment Pharmacol Ther 1999 13
381-8.
77
SPD476 for the induction of remission in
patients with mild-moderate UC
A once-daily high-dose 5-ASA formulation using a
novel multimatrix technology to delivers 1.2 g of
drug per tablet to the entire colon
280 patients 8 weeks R
Lichtenstein GR et al, A Phase III study. Am J
Gastroenterol. 2005100S-291. Abstract 787
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SPD476 for the induction of remission in
patients with mild-moderate UC
Kamm MA et al, Am J Gastroenterol.
2005100S-291. Abstract 786