Inflammatory Bowel

Disease
 Definition

Inflammatory bowel disease (IBD) is a term

encompassing a number of chronic
inflammatory disorders leading to damage of
the gastrointestinal tract.
Crohns disease
 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
 Extraintestinal Manifestations of
Inflammatory Bowel Disease
 Musculoskeletal  Ocular
 Peripheral arthritis  Uveitis
 Sacroiliitis  Scleritis
 Ankylosing spondylitis  Episcleritis
 Osteoporosis
 Vascular
 Dermatologic  Thromboembolic events
 Erythema nodosum
 Pyoderma gangrenosum  Renal
 Aphthous stomatitis  Nephrolithiasis

 Hepatobiliary Disease
 Primary sclerosing cholangitis
 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.

 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)

 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

Aphthoid ulceration of terminal ileum (small
arrows)- Note also "cobblestoning" (larger
arrows).
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. ic=ileocaecal valve.
 Endoscopy

 Upper and Lower Endoscopy

 Capsule Endoscopy
CD
CD
CD
Granuloma in CD
 ACG Practice Guidelines:
Definitions 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

 >10% weight loss

Hanauer et al A J Gastroenterology
 ACG Practice Guidelines:
Definitions 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
 ACG Practice Guidelines:
Definitions 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
 ACG Practice Guidelines:
Definitions 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-dependen”and are usually not
cosidered to be “in remission.”

Hanauer et al A J Gastroenterology 2001,96,635

 Long-term disease evolution
behavior in CD
100

90
cumulative probability(%)

80

70

60 penetrating

50

40
stricturing
30
inflammatory
20

10

0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Months

Cosnes J et al. Inflamm Bowel Dis 2002;8;244

Medical treatment of IBD
Yousef A. Qari MD,FRCPC,ABIM
Consultant Gastroenterologist
King Abdulaziz University Hospital
Jeddah, Saudi Arabia
 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
 ACG Practice Guidelines:
Recommended 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)
 Metro+Cipro (250mg 2-3 times/d +500mg 2 times/d) 76%
 Budesonide (CIR) (9mg/d)
 For ileal & Rt colonic disease 69%
 ACG Practice Guidelines:
Recommended 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.
Oral Budesonide for active CD
60

50
Patients in remission(%)

40
2 wk

30 4 wk

8 wk
20

10

(n=66) 3mg (n=67) 9mg(n=61) 15mg(n=64)

placebo Budesonide

Greenberg etal . N Engl J Med 1994;331;836-

41
 ACG Practice Guidelines:
Recommended 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

Clinical response and remission in Infliximab-
treated patients
Moderate-Severe CD:

100
81
75
% patients

placebo(n=25)
48
50
Infliximab
25 17 5mg/kg(n=27)
4
0
4-weeks clinical 4-weeks clinical
response remission

Clinical response : ≥70 points

decrease in CDAI from baseline
Targan SR et al, N Engl J Med. 1997:337:1029
Clinical remission : a CDAI of < 150
 Clinical Response at Week 52*

100
90
Proportion of patients(%)

80
P<0.001
70 P=NS
60 53
P<0.001
50 43
40
30
20 17

10
0

Single dose 5mg/kg 10mg/kg

(n=110) Q8w Q8w
(n=113) (n=111)
*Week-2
Responders
 Clinical Remission at Week 54*

60
P<0.001
Proportion of Patients(%)

50
P=NS
40 38
P<0.007 28
30

20
14
10

0
Single dose 5mg/kg 10mg/kg
(N=110) Q 8w Q 8w
(N=113) (N=112)
*Week-2 Responders
 ACG Practice Guidelines:
Recommended 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

 ACG Practice Guidelines:
Recommended treatment
Severe-Fulminant CD:

 Exclude abscess Percutaneous

 Abd US Drainage
 Abd CT Surgical

 Parentral corticosteroids equivalent to

40-60mg prednisone
 If abscess has been excluded
 If the patient has been receiving oral setroids
 ACG Practice Guidelines:
Recommended 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
 Therapeutic Options for
Perianal Fistulas in CD

Possible efficacy Proven efficacy

 Antibiotics  Infliximab
 AZT/6-MP

 Cyclosporine
 Therapeutic Options for
Perianal Fistulas in CD
AZT/6-MP
100
with Fistula response 90
80
70
% patients

60 54
50
40
30 21
20
10 6/29 22/41
0
Placebo AZT/6-MP

Compleate healing or decreased Pearson DC et al. Ann Intern Med.1995;122;132

discharge΅
 Therapeutic Options for
Perianal Fistulas in CD
Infliximab
100
% patients with compleat
closure of all Fistulas

80 P=0.001

60 55 % P=0.04

38%
40

20 13%

0
Placebo Infliximab Infliximab
5 mg/kg 10 mg/kg

Present DH et al. N Engl J Med.

 Step-up versus Top-down Trial

Newly Diagnosed Crohn (N = 129)

Step-up (N = 64) Top-down (N = 65)

steroids IFX (0/2/6) + AZA

IFX + AZA
+ IFX

+ AZA + (epis)
MTX IFX

steroids relapse steroids

steroids
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

 Azathioprine is the best conventional
drug to maintain clinical remission
Remission induced by prednisolone; tapered over 12 wk

100
Placebo (n=30)
% Patients Not Failing Trial

80
AZA 2.5 mg/kg per d (n=33)

60

40

20 ster +
AZA AZA
0
0 15
Duration of Trial (Months)

Candy S et al. Gut. 1995;37:674.

 Continuous Immunotherapy is
required to treat a Chronic Disease
Patients in clinical remission with AZA for at least 3.5 years before randomisation
1.0
7.9
Percentage of Patients in

0.8 % relapse
21.3
Remission

0.6 Remission (months)

mean ± SE
17.3 ± 0.5
0.4
15.9 ± 0.7

0.2 Azathioprine
Placebo
Months After Randomization
0.0
0 6 12 18
Months after randomisation

Lemann et al. Gastroenterol. 2005 Jun;128(7):1812-8.

 Cumulative Probability of
Surgical Intervention in CD
100
± 2 SD
80
Probability (%)

60

40

20

0
0 Dx 2 5 8 11 14 17 20
Years
Events (no.) 122 26 15 7 74 81 8 2 2 2 3 2 1

Munkholm P et al. Gastroenterology. 1993; 105:1716.

Ulcerative colitis
 Difinition

A chronic disease charecterized by diffuse

mucosal inflammation limited to the colon.
Age distribution of Ulcerative colitis in east and west
provinces of Saudi arabia
188 CASES
Age(y) at presentation
80

70

60

50
West SA
40
East SA
30

20

10

0
Less than 20 20-49 50 and above

1. Qari Y et al, under publication

2. Satti M et al, Ann Saudi Med 1996;16(6):637-640.
 Sex distribution of UC in the Gulf

80
70
60
west SA(1)
50
Cent SA(2)
40 East SA(3)
30 Kuwait(4)
Iran(5)
20
10
0
Male Female
1. Qari Y et al, under publication
4. Al-Nakib B et al. Am J Gastroenterology 1984;79:191-4
2. Hossain J et al. Ann Saudi Med 1991;11:40-6.
5. Mir-Madjlessi SH et al. Am J Gastroenterology
3. Satti M et al, Ann Saudi Med 1996;16(6):637-
1985;11:862-6.
640.
 Pattern of UC in the Gulf

100

90

80

70
West SA(1)
60
Cent SA(2)
50 East SA(3)
Kuwait(4)
40
Iran(5)
30

20

10

0
Pancolitis Left colitis

1. Qari Y et al, under publication

4. Al-Nakib B et al. Am J Gastroenterology 1984;79:191-4
2. Hossain J et al. Ann Saudi Med 1991;11:40-6.
3. Satti M et al, Ann Saudi Med 1996;16(6):637-640. 5. Mir-Madjlessi SH et al. Am J Gastroenterology 1985;11:862-6.
 Epidemiological figures comparing
East vs West

Geographic location Gulf Region West Europe

Saudi Arabia and USA

Incidence 0.5 – 2.8 / 100 000 6 -8 / 100 000

Prevalence ≈ 5 / 100 000 70 -150 /100 000

Ulcerative colitis
UC Normal
UC
UC
The goals for the management of
acute ulcerative colitis

 Induction of remission
 Prevention of relapse
 Treatment of complications
Therapeutic decisions

Ex ise
??
tiv ase

D
te ase
i ty

nt
Ac se

of ??
Di
Disease Activity
 Mild
 Moderate
 Severe
 Fulminant
Mayo score

Schroeder KW et al. N Engl J Med 1987; 317: 1625-9.

Endoscopy Photo: Sample Scores

Endoscopy score 0 Endoscopy score 1

Endoscopy score 2 Endoscopy score 3

 Severe colitis

A bloody stool frequency of > 6/day with any one of

the following:

 Tachycardia (pulse > 90 beats/min)

 Temperature (> 37.8 °C)
 Anaemia (Hg < 10.5 g/dL)
 Raised ESR (> 30 mm/h)
Extent of Disease
Activity Extent

Medical Therapy
Superiority of topical 5-ASA to placebo in
treatment of mild to moderate Distal UC.
Seven RCTs
Superiority of topical 5-ASA to placebo in
treatment of mild to moderate Distal UC.
5-aminosalicylic acid preparations (all study arms)
compared with placebo in active ulcerative colitis.

Adapted from Sutherland et al. Ann Intern Med 1993; 118: 540–9.
Combined oral and topical treatment with 5-ASA in active
extensive UC, proximal to the splenic flexure.

100
90
P =0.03
80
70 64
% Remission

(NS)
60 4.0g PO/D
50 44 43
4.0g po + 1.0g
40 34
enema/D
30
20
10
0
4 weeks 8 weeks

Marteau P et al. Gut 2005; 54: 960–5.

Topical 5-ASA have superior efficacy to oral mesalazine in
the maintenance of remission in Distal Colitis

100
90 84
80 74
68
% in remission

70
Oral Mesalazine
60 1.5g/D
50
40 32 Rectal Mesalazine
4g twice/W
30
20
10
0
One year Two years

Mantzaris GJ et al. Dis Colon Rectum 1994; 37: 58–62 .

RCTs of mesalazine vs. placebo for
preventing relapse in patients with UC

27. Ardizzone S et al.Aliment Pharmacol Ther 1999; 13: 373–9.

23. Hanauer S et al .Ann Intern Med 1996; 124: 204–11.
25. Hawkey CJ et al. Gastroenterology 1997; 112: 718–24.
24. Miner P et al. Dig Dis Sci 1995; 40: 296–304.
Compliance is a problem
Patient Non-compliance with 5-ASA
Treatment Regimens

100
90 80
% compliance to treatment

80
70
60 50
50
40
30
20
10
0
Clinical trials Community based studies

Kane SV et al. Am J Gastroenterol 2001; 96: 2929-33.

Clinical Impact of Non-adherence to therapy for UC

Greater risk of symptomatic relapse

100
% of patients relapses

90
80 (P = 0.001)
70 61
60
50
40
30
20 11
10
0
Compliant Non-compliant

Kane S. Am J Med 2003; 114: 39-43.

Clinical Impact of Non-adherence to therapy for UC

Greater risk of colorectal cancer

100
90 175 patients
80 (P < 0.001) The lifetime risk
of colorectal
% of Colon cancer

70
cancer among
60 patients with UC
50 is estimated to
40 be approximately
31
20%
30
20
10 3
0
Compliance Non-compliance
10 years follow up

Brentnall TA. Curr Opin Gastroenterol 2003; 19: 64-8.

Mesalazine 2 g gel enema is as effective as and more
convenient than mesalazine 2 g foam enema

70
P<0.005 P<0.05
60 103 patients
50 48
50
4 weeks
40
Gel enema (50)
P<0.05
26 26 Foam enema (53)
30 25

20

10 6

0
Difficulty in Abd Bloating Discomfort durig
retention adminstration

Remission rates were comparable

between the two groups.
Gionchetti P. Aliment Pharmacol Ther 1999; 13: 381-8.
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
70
59.6 280 patients
60 55.7
8 weeks R×
50

40 34 Remission
29 Improvement
30 25.9

20
12.9
10

0
1.2g BID 4.8g OD Placebo

Lichtenstein GR et al, A Phase III study. Am J Gastroenterol. 2005;100:S-291. [Abstract #787]

SPD476* for the induction of remission in
patients with mild-moderate UC
80
70 64.7
60.7
60 55.8

50
40.5 41.2
Remission
40 32.6 Improvement
30
20
10
0
2.4g OD 4.8g OD 800mg TID

Kamm MA et al, Am J Gastroenterol. 2005;100:S-291. [Abstract #786]