Inflammatory Bowel Disease

Inflammatory Bowel Inflammatory Bowel DiseaseDisease

DefinitionDefinition

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

Crohns diseaseCrohns disease

Symptoms of CDSymptoms of CD

The presentation depends on the site, extent, severity, and The presentation depends on the site, extent, severity, and complications of intestinal and extraintestinal disease.complications of intestinal and extraintestinal disease.

Fevers, night sweats, and weight loss.Fevers, night sweats, and weight loss.

Abdominal pain Abdominal pain

Nausea and vomiting Nausea and vomiting

DiarrheaDiarrhea

Rectal bleedingRectal bleeding

Extraintestinal Manifestations of Extraintestinal Manifestations of

Inflammatory Bowel DiseaseInflammatory Bowel Disease MusculoskeletalMusculoskeletal

Peripheral arthritis Peripheral arthritis Sacroiliitis Sacroiliitis Ankylosing spondylitis Ankylosing spondylitis OsteoporosisOsteoporosis

DermatologicDermatologic Erythema nodosum Erythema nodosum Pyoderma gangrenosum Pyoderma gangrenosum Aphthous stomatitisAphthous stomatitis

Hepatobiliary DiseaseHepatobiliary Disease Primary sclerosing cholangitisPrimary sclerosing cholangitis

OcularOcular Uveitis Uveitis Scleritis Scleritis EpiscleritisEpiscleritis

VascularVascular Thromboembolic eventsThromboembolic events

RenalRenal NephrolithiasisNephrolithiasis

Physical Examination in CDPhysical Examination in CD

Weight loss and pallor.Weight loss and pallor. Clubbing of the fingers.Clubbing of the fingers. Abdominal distension Abdominal distension

Tenderness in the area of involvement Tenderness in the area of involvement

Abnormal bowel sounds. Abnormal bowel sounds.

Presence of an inflammatory mass are common. Presence of an inflammatory mass are common.

Perianal abscess, fistula, skin tags, or anal stricture.Perianal abscess, fistula, skin tags, or anal stricture.

Laboratory StudiesLaboratory Studies

AnemiaAnemia Deficiencies of iron, vitamin B12, or folic acid Deficiencies of iron, vitamin B12, or folic acid Anemia of chronic disease. Anemia of chronic disease.

LeukocytosisLeukocytosis ThrombocytosisThrombocytosis Elevated ESR and C-reactive protein levels Elevated ESR and C-reactive protein levels Decreased Serum albumin levels Decreased Serum albumin levels Urinalysis commonly demonstrates calcium oxalate crystals.Urinalysis commonly demonstrates calcium oxalate crystals. Stoolanalysis for fecal leukocytesStoolanalysis for fecal leukocytes Serologic markers with high specificity for CD.Serologic markers with high specificity for CD.

Anti-Anti-Saccharomyces cerevisiaeSaccharomyces cerevisiae antibody(ASCA) antibody(ASCA) Antibody to the outer core membrane of Antibody to the outer core membrane of E. coliE. coli (OmpC) (OmpC)

Imaging StudiesImaging Studies

Plain abdominal x- rayPlain abdominal x- ray Barium studiesBarium studies

Small bowel enema (enteroclysis) / follow-throughSmall bowel enema (enteroclysis) / follow-through Large bowel enemaLarge bowel enema

U/S Abdomen and Pelvis / Transrectal U/SU/S Abdomen and Pelvis / Transrectal U/S CT Abdomen and PelvisCT Abdomen and Pelvis MRIMRI

CDCD

Aphthoid ulceration of terminal ileum (small arrows)- Note also "cobblestoning" (larger arrows).

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.

EndoscopyEndoscopy

Upper and Lower EndoscopyUpper and Lower Endoscopy Capsule EndoscopyCapsule Endoscopy

Granuloma in CDGranuloma in CD

ACG Practice Guidelines:ACG Practice Guidelines:Definitions of Disease SeverityDefinitions of Disease Severity

Ambulatory patientsAmbulatory patients Patients who are able to tolerate oral alimentationPatients who are able to tolerate oral alimentation Patients without manifestations ofPatients without manifestations of

DehydrationDehydration Toxicity ( high fever, rigors, prostration )Toxicity ( high fever, rigors, prostration ) Abdominal tendernessAbdominal tenderness Painful massPainful mass Obstruction Obstruction >10% weight loss>10% weight loss

Mild – Moderate CD :

Hanauer et al A J Gastroenterology 2001,96,635

ACG Practice Guidelines:ACG Practice Guidelines:Definitions of Disease Severity (cont.)Definitions of Disease Severity (cont.)

Patients who have failed to respond to treatment Patients who have failed to respond to treatment for mild-moderate diseasefor mild-moderate disease

Patients with more prominent symptom of:Patients with more prominent symptom of: FeverFever Significant weight lossSignificant weight loss Abdominal pain or tendernessAbdominal pain or tenderness Intermittent nausea or vomiting (Intermittent nausea or vomiting (without without

obstructive findingsobstructive findings)) Significant anemiaSignificant anemia

Moderate-Severe CD:


ACG Practice Guidelines:ACG Practice Guidelines:Definitions of Disease Severity (cont.)Definitions of Disease Severity (cont.)

Patients with persistent symptoms despite the Patients with persistent symptoms despite the introduction of steroids as out patientintroduction of steroids as out patient

Individuals presenting with: Individuals presenting with: High feverHigh fever Persistent vomitingPersistent vomiting Evidence of intestinal obstructionEvidence of intestinal obstruction Rebound tenternessRebound tenterness CachexiaCachexia, or, or Evidence of Evidence of abscessabscess

Sever –Fulminant CD:


ACG Practice Guidelines:ACG Practice Guidelines:Definitions of Disease activityDefinitions of Disease activity

Patients who are asymptomatic or without Patients who are asymptomatic or without inflammatory sequelaeinflammatory sequelae

Patients who have responded to acute medical Patients who have responded to acute medical interventionintervention oror have udergone surgical resection have udergone surgical resection without gross evidence of residual diseasewithout gross evidence of residual disease

NB:NB: Patients requiring steroids to maintain well-being are Patients requiring steroids to maintain well-being are considered to be “steroid-dependen”and are usually considered to be “steroid-dependen”and are usually notnot cosidered to be “in remission.” cosidered to be “in remission.”

CD in remission:


Long-term disease evolution Long-term disease evolution behavior in CDbehavior in CD

penetrating

stricturing

0

10

20

30

40

50

60

70

80

90

100

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

Months

cu

mu

lati

ve

pro

ba

bili

ty(%

)

inflammatory

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

Medical treatment of IBDMedical treatment of IBD

Yousef A. Qari Yousef A. Qari MD,FRCPC,ABIMMD,FRCPC,ABIM

Consultant GastroenterologistConsultant GastroenterologistKing Abdulaziz University HospitalKing Abdulaziz University Hospital

Jeddah, Saudi Arabia Jeddah, Saudi Arabia

Current Expectations for IBD TherapyCurrent Expectations for IBD Therapy

Induce clinical remissionInduce clinical remission Maintain clinical remissionMaintain clinical remission Improve quality of lifeImprove quality of life

PlusPlus Heal mucosaHeal mucosa Decrease hospitalization / surgery / overall costsDecrease hospitalization / surgery / overall costs Minimize disease- related and therapy-related Minimize disease- related and therapy-related

complicationscomplications

ACG Practice Guidelines:ACG Practice Guidelines:Recommended treatmentRecommended treatment

AminosalicylatesAminosalicylates Sulphasalazine (3-6g/d)Sulphasalazine (3-6g/d) Mesalamine (3.2-4.0g/d) Mesalamine (3.2-4.0g/d) 40-50%40-50%

Antibiotics (CD involving colon)Antibiotics (CD involving colon) Metronidasole (10-20mg/kg) 50%Metronidasole (10-20mg/kg) 50% Ciprofloxacin (1g/d)Ciprofloxacin (1g/d) Metro+Cipro (250mg 2-3 times/d +500mg 2 times/d) Metro+Cipro (250mg 2-3 times/d +500mg 2 times/d) 76%76%

Budesonide (CIR) (9mg/d)Budesonide (CIR) (9mg/d) For ileal & Rt colonic disease For ileal & Rt colonic disease 69%69%

Mild – Moderate CD :

Remission


CorticosteroidsCorticosteroids Appropriate antibiotics therapy or drainageAppropriate antibiotics therapy or drainage

(surgical/percutaneous) required for infection (surgical/percutaneous) required for infection or abscessor abscess

InflximabInflximab infusion infusion Effective adjunctEffective adjunct Possible alternative to steroid therapy in selected Possible alternative to steroid therapy in selected

patients in whom corticosteroids are patients in whom corticosteroids are contraindicated or ineffective.contraindicated or ineffective.

Moderate –Severe CD

Oral Budesonide for active CDOral Budesonide for active CD

0

10

20

30

40

50

60

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

placebo Budesonide

Pat

ien

ts i

n r

emis

sio

n(%

)

2 wk

4 wk

8 wk

Greenberg etal . N Engl J Med 1994;331;836-41


CorticosteroidsCorticosteroidsBudesonide 9mg/d Budesonide 9mg/d ororPrednisone (0.5-0.75mg/kg) Prednisone (0.5-0.75mg/kg) or or 40mg/d40mg/d

5o-70% remission rate in 8-12 weeks5o-70% remission rate in 8-12 weeks Until resolution of symptoms and resumption of weight Until resolution of symptoms and resumption of weight

gain, generally 7-28 days.gain, generally 7-28 days. Steroid refractory & steroid dependent ≈ 50%Steroid refractory & steroid dependent ≈ 50%

SmookingSmooking Colonic diseaseColonic disease

Not Not effective for maintenanceeffective for maintenance

Moderate –Severe CD:

Clinical response and remission in Infliximab-Clinical response and remission in Infliximab-treated patientstreated patients

17

4

48

81

0

25

50

75

100

4-weeks clinicalresponse

4-weeks clinicalremission

% p

ati

en

ts placebo(n=25)

Infliximab5mg/kg(n=27)

Clinical response : ≥70 points decrease in CDAI from baseline

Clinical remission : a CDAI of < 150

Targan SR et al, N Engl J Med. 1997:337:1029

Moderate-Severe CD:

Clinical Response at Week 52*Clinical Response at Week 52*

53

43

17

0

10

20

30

40

50

60

70

80

90

100

Single dose(n=110)

5mg/kg Q8w (n=113)

10mg/kg Q8w

(n=111)

Pro

po

rtio

n o

f p

atie

nts

(%)

P<0.001

P<0.001

P=NS

*Week-2 Responders

Clinical Remission at Week 54*Clinical Remission at Week 54*

38

28

14

0

10

20

30

40

50

60

Pro

po

rtio

n o

f P

ati

en

ts(%

)

Single dose(N=110)

5mg/kgQ 8w

(N=113)

10mg/kgQ 8w

(N=112)

P<0.007

P<0.001

P=NS

*Week-2 Responders


Hospitalization required for :Hospitalization required for : patients with persistent symptoms despite introduction of oral patients with persistent symptoms despite introduction of oral

steroids or infliximabsteroids or infliximab

Patients presenting with high fever, frequent vomiting, evidence Patients presenting with high fever, frequent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or an of intestinal obstruction, rebound tenderness, cachexia, or an abscessabscess

Surgical consultation is warranted for patients with Surgical consultation is warranted for patients with obstruction or tender abdominal mass.obstruction or tender abdominal mass.

Severe-Severe-Fulminant CD:Fulminant CD:

Hanaur S et al. Am J Gastroenterology; 96; 635


Exclude abscessExclude abscess Abd USAbd US Abd CTAbd CT

Parentral corticosteroids equivalent to Parentral corticosteroids equivalent to 40-60mg prednisone40-60mg prednisone If abscess has been excludedIf abscess has been excluded If the patient has been receiving oral setroidsIf the patient has been receiving oral setroids


Drainage

PercutaneousSurgical


Parentral broad spectrum antibioticsParentral broad spectrum antibiotics High feverHigh fever Toxic appearanceToxic appearance Inflammatory massInflammatory mass

Nutritional support: (Elemental or TPN)Nutritional support: (Elemental or TPN) TPN in addition to steroids plays no specific roleTPN in addition to steroids plays no specific role IndicationsIndications

For patients unable to maintain nutritional requirments For patients unable to maintain nutritional requirments after 5-7 daysafter 5-7 days

Preoperative managementPreoperative management Pediatric age groupsPediatric age groups


Therapeutic Options for Therapeutic Options for Perianal Fistulas in CDPerianal Fistulas in CD

Possible efficacyPossible efficacy Antibiotics Antibiotics AZT/6-MP AZT/6-MP

CyclosporineCyclosporine

Proven efficacyProven efficacy InfliximabInfliximab

Therapeutic Options forTherapeutic Options for Perianal Fistulas in CD Perianal Fistulas in CD

AZT/6-MP

21

54

0

10

20

30

40

50

60

70

80

90

100

Placebo AZT/6-MP

% p

atie

nts

with

Fis

tula

re

spo

nse

6/29 22/41

Compleate healing or decreased discharge΅

Pearson DC et al. Ann Intern Med.1995;122;132

Therapeutic Options forTherapeutic Options for Perianal Fistulas in CD Perianal Fistulas in CD

38

55

13

0

20

40

60

80

100

Placebo Infliximab 5 mg/kg

Infliximab10 mg/kg

% p

atie

nts

with

com

plea

t c

losu

re o

f al

l Fis

tula

s

%

%

%

Infliximab

Present DH et al. N Engl J Med. 1999;34;1398

P=0.001

P=0.04

Newly Diagnosed Crohn (N = 129)

Step-up (N = 64)

steroids

Top-down (N = 65)

IFX (0/2/6) + AZA

steroids

steroids

+ AZAMTX

+ IFX IFX + AZA

+ (epis) IFX

steroids

Step-up versus Top-down TrialStep-up versus Top-down Trial

relapserelapse

Step Up treatment paradigm driven by Step Up treatment paradigm driven by cost, safety and adverse eventscost, safety and adverse events

Aminosalicylates

SteroidsElemental dietAntibiotics

Infliximab

Immunosuppressives

The classical Step-Up-treatment paradigm

Surgery

Azathioprine is the best conventional Azathioprine is the best conventional drug to maintain clinical remissiondrug to maintain clinical remission

80

60

40

20

0

Placebo (n=30)

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

60

40

20

0

Placebo (n=30)

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

60

40

20

0

Placebo (n=30)

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

% P

atie

nts

No

t F

aili

ng

Tri

al

Duration of Trial (Months)

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

0 15

Remission induced by prednisolone; tapered over 12 wk

100

ster +AZA AZA

Continuous Immunotherapy is Continuous Immunotherapy is required to treat a Chronic Diseaserequired to treat a Chronic Disease

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18

Months After Randomization

Per

cent

age

of P

atie

nts

in

Rem

issi

on

Azathioprine

Placebo

Remission (months)mean ± SE17.3 ± 0.515.9 ± 0.7

% relapse

7.9

21.3

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

Months after randomisation

Patients in clinical remission with AZA for at least 3.5 years before randomisation

Cumulative Probability of Cumulative Probability of Surgical Intervention in CDSurgical Intervention in CD

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

Years

Pro

babi

lity

(%)

Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1

0

20

40

60

80

100

0 2 5 8 11 14 17 20

± 2 SD

Dx

Ulcerative colitisUlcerative colitis

DifinitionDifinition

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

Age distribution of Ulcerative colitis in east and west Age distribution of Ulcerative colitis in east and west provinces of Saudi arabia provinces of Saudi arabia 188 CASES188 CASES

0

10

20

30

40

50

60

70

80

Less than 20 20-49 50 and above

West SA

East SA

Age(y) at presentation

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 GulfSex distribution of UC in the Gulf

0

10

20

30

40

50

60

70

80

Male Female

west SA(1)

Cent SA(2)

East SA(3)

Kuwait(4)

Iran(5)

1. Qari Y et al, under publication2. Hossain J et al. Ann Saudi Med 1991;11:40-6.3. Satti M et al, Ann Saudi Med 1996;16(6):637-

640.

4. Al-Nakib B et al. Am J Gastroenterology 1984;79:191-4 5. Mir-Madjlessi SH et al. Am J Gastroenterology 1985;11:862-6.

Pattern of UC in the GulfPattern of UC in the Gulf

0

10

20

30

40

50

60

70

80

90

100

Pancolitis Left colitis

West SA(1)

Cent SA(2)

East SA(3)

Kuwait(4)

Iran(5)

1. Qari Y et al, under publication

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.

.

4. Al-Nakib B et al. Am J Gastroenterology 1984;79:191-4 5. Mir-Madjlessi SH et al. Am J Gastroenterology 1985;11:862-6.

Epidemiological figures comparing Epidemiological figures comparing East vs WestEast 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

Ulcerative colitisUlcerative colitis

UC NormalUC Normal

The goals for the management of The goals for the management of acute ulcerative colitisacute ulcerative colitis

Induction of remissionInduction of remission Prevention of relapse Prevention of relapse Treatment of complicationsTreatment of complications

Therapeutic decisionsTherapeutic decisions

Disea

se

Activ

ity ?

?

Extent of

Disease ??

Disease ActivityDisease Activity

MildMild ModerateModerate SevereSevere FulminantFulminant

Mayo score

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

Endoscopy Photo: Sample ScoresEndoscopy Photo: Sample Scores

Endoscopy score 1Endoscopy score 1Endoscopy score 0Endoscopy score 0

Endoscopy score 2Endoscopy score 2 Endoscopy score 3Endoscopy score 3

Severe colitisSevere colitis

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

Tachycardia (pulse > 90 beats/min)Tachycardia (pulse > 90 beats/min) Temperature (> 37.8 °C)Temperature (> 37.8 °C) Anaemia (Hg < 10.5 g/dL)Anaemia (Hg < 10.5 g/dL) Raised ESR (> 30 mm/h) Raised ESR (> 30 mm/h)

Extent of Disease

Medical TherapyMedical Therapy

Activity Extent

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.

344344

64

0

10

20

30

40

50

60

70

80

90

100

4 weeks 8 weeks

% R

emis

sio

n

4.0g PO/D

4.0g po + 1.0genema/D

Marteau P et al. Gut 2005; 54: 960–5.

(NS)

P =0.03

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

68

32

8474

0102030405060708090

100

One year Two years

%

in r

emis

sio

n

Oral Mesalazine1.5g/D

Rectal Mesalazine4g twice/W

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 problemCompliance is a problem

Patient Non-compliance with 5-ASA Patient Non-compliance with 5-ASA Treatment RegimensTreatment Regimens

80

50

0

10

20

30

40

50

60

70

80

90

100

% c

om

pli

ance

to

tre

atm

ent

Clinical trials Community based studies

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

Clinical Impact of Non-adherence to therapy for UCClinical Impact of Non-adherence to therapy for UC

11

61

0

10

20

30

40

50

60

70

80

90

100

% o

f p

ati

en

ts r

ela

ps

es

Compliant Non-compliant

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

Greater risk of symptomatic relapse

(P = 0.001)

Clinical Impact of Non-adherence to therapy for UCClinical Impact of Non-adherence to therapy for UC

3

31

0

10

20

30

40

50

60

70

80

90

100

% o

f C

olo

n c

an

ce

r

Compliance Non-compliance

10 years follow up

Greater risk of colorectal cancer

(P < 0.001)

175 patients The lifetime risk of colorectal cancer among patients with UC is estimated to be approximately 20%

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

Mesalazine 2 g Mesalazine 2 g gelgel enema is as effective as and more enema is as effective as and more

convenient than mesalazine 2 g convenient than mesalazine 2 g foam foam enemaenema

6

26 2625

50 48

0

10

20

30

40

50

60

70

Difficulty inretention

Abd Bloating Discomfort durigadminstration

Gel enema (50)

Foam enema (53)P<0.05

P<0.005 P<0.05

103 patients

4 weeks

Remission rates were comparable between the two groups.

Gionchetti P. Aliment Pharmacol Ther 1999; 13: 381-8.

SPD476* for the induction of remission in SPD476* for the induction of remission in

patients with mild-moderate UCpatients with mild-moderate UC

3429

12.9

55.759.6

25.9

0

10

20

30

40

50

60

70

1.2g BID 4.8g OD Placebo

Remission

Improvement

280 patients

8 weeks R×

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

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

SPD476* for the induction of remission in SPD476* for the induction of remission in patients with mild-moderate UCpatients with mild-moderate UC

40.5 41.2

32.6

60.764.7

55.8

0

10

20

30

40

50

60

70

80

2.4g OD 4.8g OD 800mg TID

Remission

Improvement

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

Inflammatory Bowel Disease

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