Crohn

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Crohns DiseaseOverview
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Etiology of Crohns Disease
Several Theories Exist
Host (Immune response)
Nonspecific inflammation Tissue
injury Restitution and repair
Genetic Susceptibility
Environmental Factors
Elson CO et al. In Proceedings of V
International Symposium on Inflammatory Bowel
Diseases. 1998. In Press.
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Evidence of the Role of TNFa in IBD

• Mucosal production of TNFa is greater in patients
  with IBD than in controls in most, but not all
  reports1,2
• The number of cells producing TNFa is greater in
  patients with IBD than in controls2,3
• TNFa is increased throughout the intestinal
  mucosa in patients with UC and throughout both
  the mucosa and submucosa of patients with CD1

1. Murch SH et al. Gut. 1993341705-1709. 2.
Reinecker H-C et al. Clin Exp Immunol.
199394174-181. 3. Breese ES et al.
Gastroenterology. 19941061455-1466.
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Evidence of the Role of TNFa in IBD

• Increased concentrations of TNFa have been
  detected in the stools of children with active
  disease1
• Serum levels of soluble TNF receptors are
  increased in patients with CD as a result of
  T-cell activation2

1. Braegger CP et al. Lancet. 199233989-91. 2.
Stronkhorst A et al. Gastroenterology.
1994106(Suppl 4)A779. Abstract.
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Genetic Influence in IBD

• Racial and ethnic differences in incidence
• Increased incidence among monozygotic twins
  (primarily in patients with CD)
• Association with certain genetic syndromes

Yang H, Rotter JI. In Inflammatory Bowel
Disease. From Bench to Bedside. 199332-64.
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Familial Patterns of Inheritance

• Approximately 10 of patients have positive
  family history
• 210 risk if first-degreerelatives affected
• 50100-fold increase in prevalence for children
  of patients with IBD

Yang H, Rotter JI. In Inflammatory Bowel
Disease. From Bench to Bedside. 199332-64.
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Microbial Mucosal Immune Interactions

• Animal models support the view that IBD is caused
  by genetically determined dysregulation in
  mucosal immune response to normal gut microflora
  (luminal antigens)
• Intestinal mucosa relatively free of adherent
  bacteria

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Microbial Mucosal Immune Interactions

• IBD patients have increased numbers of diverse
  bacterial antigens within the mucosa
• Farrell and LaMont Gastro Clin NA 20023141.
• Increased numbers of specific species
  (Bacteroides, Fusobacteria) may be a determinant
  of post-op recurrence
• Neut et al. Am JGastroenterol 200297939.
• Mucosa associated E coli strains alter
  permeability in IEC monlayers
• Rocha et al. Surgery 200113065.

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Pathogenesis of Crohns Disease
Podolsky, DK NEJM 2002347417-29.
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Tobacco Smoking and IBD

• Smoking shown to be protective in UC and has
  adverse effect on clinical course of CD
• Inverse association in UC and CD likely
  reflective of differences in pathogenesis

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Natural History What Do We Know ?

• Complications increase with time and depend on
  location and behavior
• Predictable post-operative recurrence
• Negative impact of smoking and NSAIDs

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Effect of Disease Location on Behavior of CD in
Females
Freeman H. J. Clin Gastroenterology 200337, 3
216-219
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Chrons Disease Activity IndexCDAI

• Chrons Disease
• Endoscopic Index Severity
• CDEIS

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Crohns Disease Activity Index

• Scoring
• Maximum score 600
• Remission lt 150
• Moderate activity 200 450
• Severe activity gt 450

Best WR et al. Gastroenterology. 197670439-444.
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Crohns Disease Endoscopic Index of Severity
Variables

• Size of lesion(s)
• Measured in centimeters
• Presence of stenoses
• Ulcerated
• Nonulcerated

• Disease location
• Rectum
• Sigmoid and left colon
• Transverse colon
• Right colon
• Ileum
• Depth of lesion(s)
• Superficial
• Deep

Mary JY, Modigliani R. Gut. 198930983-989.
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Crohns Disease Endoscopic Index of Severity
CDEIS

• Index construction and calculation
• CDEIS Sum of 12 x ISRCF (deep ulceration)
• 6 x ISRCF (superficial ulceration)
• ASSD (segmented surface disease)
• ASSU (segmented surface ulcerated)
• 3 x PRES (ulcerated stenosis)
• 3 x PRES (nonulcerated stenosis)

ISRCF, individual segmental rectocolonic
frequency ASSD, average segmental surfaces
involved by disease ASSU, average segmental
surfaces involved by ulceration PRES, present.
Mary JY, Modigliani R. Gut. 198930983-989.
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Therapeutic Endpoints of Acute Therapy for CD

• CDAI score lt 150 (absence of inflammatory
  symptoms)
• Endoscopic evidence of mucosal response
  (reduction in CDEIS score)
• Highest score 14.9
• Lowest score 0
• Corticosteroid withdrawal
• Improved quality of life

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Goals of Therapy

• Inducing remission
• Maintaining remission
• Healing mucosa
• Restore and maintain nutrition
• Maintain quality of life
• For those requiring surgery, select optimal
  timing for surgical intervention

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Current Step-Up Approach to Crohns Disease
(CD) Therapy
Severe
Infliximab
Surgery
Bowel Rest
Moderate
AZA/6-MP/ MTX
Prednisone
Corticosteroids
Budesonide
Mild
Antibiotics
? ?
Aminosalicylates
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Its not just inducing remission that counts
the trick is holding on to it.
Sachar DB. Inflamm Bowel Dis. 20006329.
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Potential Maintenance of Remission Therapies for
Crohns Disease

• Sulfasalazine
• Mesalamine
• Antibiotics
• Corticosteroids
• Budesonide
• Azathioprine, 6-Mercaptopurine
• Methotrexate
• Infliximab

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Long-term Maintenance of Remission in CD

• Oral aminosalicylates
• Topical aminosalicylates
• Systemic corticosteroids
• Corticosteroids with low systemic
• bioavailability (budesonide)
• Immunosuppressants
• Cyclosporine
• Methotrexate
• Azathioprine/6-mercaptopurine

, questionable , weak , moderate ,
strong , none.
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Mesalamine in Medically Induced Remission
Date
Study
1990
1- Thomson
1992
2- Prantera
1992
3- Brignola
1993
4- Gendre
1994
5- Bresci
1995
6- Thomson
1995
7- Arber
1996
8- Modigliani
1997
9- Sutherland
1997
10- De Franchis
Overall 1371
Favors Treatment
Favors Control
Camma C et al. Gastroenterol 19971131465-73.
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Mesalamine in Surgically Induced Remission
Overall 411
Overall Including Lochs (2000),
excluding Caprilli (1994, 1 above)
Favors Treatment
Favors Control
Camma C et al. Gastroenterol 1997113 1465-73.
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Azathioprine Maintenance of Steroid- Induced
Remission for Crohns Disease

• 63 patients with active disease
• Prednisolone tapering schedule (1 mg/kg0/12
  weeks)
• Randomized 2.5 mg/kg azathioprine vs placebo
• Outcome treatment success (induction and
  maintenance of remission)

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Azathioprine
Placebo
80
On trial
60
40
20
0
0
1
3
5
7
9
11
13
15
Duration of trial (months)
Candy S. et al. Gut 1995, 37674-8.
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AZA 6-MP Maintenance of Remission

• Six controlled trials have evaluated the efficacy
  of AZA or 6-MP for maintenance of remission
• Five of these studies were included in a
  meta-analysis
• The overall rate of remission maintenance was
  higher in patients receiving AZA or 6-MP compared
  to placebo (67 vs. 52)
• Maintenance of remission was dose-dependent
• In studies that evaluated steroid use, patients
  receiving 2.5 mg/kg/day AZA were significantly
  more likely to reduce steroid consumption (87
  vs. 53)

Pearson et al. Ann Intern Med 1995 123132-42.
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AZA and 6-MP Questions ?

• How long ?
• Combined therapy with infliximab ?

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Relapse Rate After Azathioprine Withdrawal
According to Duration of Remission on Azathioprine
80
60
7
13

Maintain
6
of Relapse at 2 yr
n.s.
40
Stopped
7


4
n.s.
20

150
24
57
99
35
12
0
0-1
1 to 2
2 to 3
3 to 4
4 to 5
gt5
Duration of Remission on Azathioprine (years)
Bouhnik et al. Lancet 1996347215-9.
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TNF Neutralizing Drugs
Infliximab chimeric mouse monoclonal anti-TNF
human IgG1 protein
Etanercept recombinant human p75 TNF receptor Fc
fusion protein.
VL
VH
Ck
CH1
Rh p75 TNFR
CH2
CH2
CH3
CH3
Mouse
Rh p75 TNF Receptor
Human IgG1 Fc
Human IgG1 Fc
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TNF Metabolism
Soluble TNF
p75 TNF receptor
p55 TNF receptor
Membrane bound TNF
extracellular
intracellular
TACE
Death domain (TRADD)
TRAF2
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Infliximab but Not Etanercept Is Effective in
Crohns Disease
Sandborn et al. Gastroenterology 2001
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Etanercept and Infliximab Neutralize Recombinant
Human TNF Effectively
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Only infliximab Binds memTNF on Activated
Peripheral Lymphocytes
medium
infliximab
c17-1a
etanercept
24
Counts
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GaH-FITC
Medium
Infliximab
Etanercept
c17-1a
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Only Infliximab Binds memTNF On Activated Lamina
Propria Lymphocytes From Crohns Disease Patients
c17-1A
Infliximab
Etanercept
Antibody concentration (µg/ml)
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Only Infliximab Induces Apoptosis in Activated
Lymphocytes
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Infliximab Activates Caspase 3, Etanercept Does
Not.
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Infliximab but Not Etanercept Induces Apoptosis
in Activated Crohns LPMNC in a MLR
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ACCENT I II Baseline Patient Characteristics
ACCENT I ACCENT I ACCENT I ACCENT II ACCENT II
Group I Group II Group III Group I Group II
Patients 188 192 193 143 139
Age 36 35 35 38 38
Disease duration 7.5 7.5 8.7 12.0 10.7
Previous resection 51 52 50 56 55
IBDQ 126 126 131 167 155
CRP mg/dL 0.6 0.8 0.9 0.7 0.7
Steroids 51 51 51 29 29
Immunomodulators 32 21 23 35 34
All values are median
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Baseline Patient Characteristics

• Typical Crohns disease population with
  moderately to severely active disease
• Median CDAI (range) 297 (193 - 488)
• Median IBDQ (range) 127 (56 - 200)
• Patients receiving corticosteroids 62
• Patients receiving immunomodulators 29
• Patients were well balanced for other parameters

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ACCENT I II
Endpoint Definitions

• ACCENT I
• Clinical response reduction of ? 25 and ? 70
  points in CDAI
• Loss of response CDAI ? 175, increased by ? 35,
  ? 70 points higher than qualifying CDAI
• Clinical remission CDAI lt 150
• ACCENT II
• Fistula response ? 50 reduction from baseline
  in the number of draining fistulas
• Loss of fistula response lt 50 reduction in the
  number of draining fistula from baseline over 4
  weeks
• Complete fistula response absence of any
  draining fistula
• CDAI remission CDAI lt 150

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ACCENT I Study Design
All Patients (N573)
Infusion
Infliximab 5mg/kg
Week 0
Non-Responders at Week 2 N238 (42)
Responders at Week 2 N335 (58)
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All Patients (N573) Clinical Response Through
Week 10
Single Dose vs 3-Dose Induction
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Response to Infliximab Therapy Among Randomized
Patients
(N573)
80
58.5
60
of Patients
40
22.5
18.0
20
0
Rapid Responders
Delayed
Non-responders
(N385)
Responders
(N103)
(N135)
CSR 1849.
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Patients Who Crossed Over
MS 10.
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ACCENT I Patients in Clinical Response Through
Week 54
Responders
All Randomized
14
18
22
26
30
34
38
42
46
50
54
14
18
22
26
30
34
38
42
46
50
54
79
ACCENT I Patients in Clinical Remission
Responders
All Randomized
14
18
22
26
30
34
38
42
46
50
54
14
18
22
26
30
34
38
42
46
50
54
80
ACCENT I CDAI Was Lower With Infliximab
Maintenance Therapy
Responders
All Randomized
Median CDAI
Median CDAI
Week
Week
Group I (n110)
Group II (n113)
Group III (n112)
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ACCENT I Average Daily Corticosteroid Dose
Through Week 54
20
15
10
Median Corticosteroid Dose
5
0
0
6
10
14
22
30
38
46
54
2
4
Weeks
Group I (N89)
Group II (N95)
Group III (N95)
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Reduction of Hospitalizations/ Surgeries with
Infliximab
P0.06
P0.14
Plt0.05
Plt0.01
Rubenstein JH. J Clin Gastroenterol
200235(2)151-6.
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Reduction in ER Visits/Procedures with Infliximab
P0.01 for all endpoints
Rubenstein JH. J Clin Gastroenterol
200235(2)151-6.
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ACCENT II Study Design
All Patients (N 306)
Infusion Week 0 Week 2 Week 6
Infliximab 5 mg/kg
Not Randomized (N 24)
Placebo Maintenance (N143)
Infliximab Maintenance 5 mg/kg (N 139)
Responders (N 99)
Week 14
Non-responders (N 44)
Responders (N 96)
Non-responders (N 43)
Week 22 Week 30 Week 38 Week 46 Week 54
Crossover to 5 mg/kg
Crossover to 5 mg/kg
Crossover to 10 mg/kg
Crossover to 10 mg/kg
Evaluation
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ACCENT II Baseline Patient Characteristics
ACCENT II ACCENT II
Group I Group II
Patients 143 139
Age 38 38
Disease duration 12.0 10.7
Previous resection 56 55
IBDQ 167 155
CRP mg/dL 0.7 0.7
Steroids 29 29
Immunomodulators 35 34
All values are median
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ACCENT II Endpoint
Definitions

• ACCENT II
• Fistula response ? 50 reduction from baseline
  in the number of draining fistulas
• Loss of fistula response lt 50 reduction in the
  number of draining fistula from baseline over 4
  weeks
• Complete fistula response absence of any
  draining fistula
• CDAI remission CDAI lt 150

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ACCENT II Patients in Fistula Response
Complete Fistula Response
Complete Fistula Response
14
18
22
26
30
34
38
42
46
50
54
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Duration of Infliximab Maintenance vs. Episodic
Treatment
ACCENT I
ACCENT II
(n146)
(n154)
(n193)
(n133)
(n125)
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ACCENT I Endoscopic Substudy

• Patients
• N99
• 25 European sites
• 2-week responders and recipients of episodic
  retreatment
• Endoscopic Assessment
• CDEIS Weeks 0,10, and 54
• Definition of healing
• Mucosal ulceration at Week 0 and no mucosal
  ulceration at follow-up colonoscopies

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Evaluations

• CDAI scores were calculated at baseline and
• Weeks 2, 6, 10, 14, 22, 30, 38, 46, 54
• Data regarding lesions were calculated by
  endoscopic examination of the rectum, sigmoid and
  left colon, transverse colon, right colon, cecum,
  and ileum at baseline, Week 10, and Week 54
• Reduction of ulcerations was also assessed using
  the CDEIS (higher CDEIS scores indicate greater
  disease activity)
• Mucosal healing was defined as presence of
  mucosal ulceration (aphthoid, superficial or
  shallow, deep, or ulcerated stenosis) at Week 0
  and absence at follow-up visits

Rutgeerts et al, DDW 2002 Abstract W1367.
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Patients Demonstrating Mucosal Healing
CDEIS Median Chg from BL to Week 54
CDEIS Median Chg from BL to Week 10
Infliximab
Infliximab
5 mg/kg
10 mg/kg
Placebo
0
-1
-2
-3
-4
-5
-6
Rutgeerts et al, DDW 2002 Abstract W1367.
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Maintenance Infliximab vs Episodic Therapy
Patients with Healed Mucosa
70
Week 2 Responders
P0.007
60
P0.026
53
46
50
P0.01
40
of Patients
31
30
20
7
10
0
0
N17
N32
N14
N11
N15
Week 10
Week 54
Single Infusion
Infliximab 5 mg/kg
Infliximab 10 mg/kg
Rutgeerts et al, DDW 2002 Abstract W1367.
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Endoscopic Findings for a 5 mg/kg Infliximab
Maintenance Patient
Week 54
Baseline
Week 10
Rutgeerts et al, DDW 2002 Abstract W1367.
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Crohns-Related Hospitalization and Surgery Rates
and ICU Days by Mucosal Healing
200
150
100
50
0
95
Infliximab Safety
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Infliximab Patient Exposure
Period Ending EU Worldwide PSUR
1 2/00 4,975 22,032
PSUR 2 8/00 13,883 76,400 PSUR
3 2/01 26,959 135,693 PSUR 4 8/01 49,948 199,
943 PSUR 5 2/02 75,853 271,152 PSUR 6 8/02
103,553 344,117 PSUR 7 2/03
127,577 432,648
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Cumulative Exposure and Reporting Rates for
Tuberculosis
PSUR Expos/ Expos Cases
PRR Cumul PRR period
Cumul Cases Cumul 1
22,032 34,354 1
0.00 2 0.01 2
44,786 79,140 15 0.03
17 0.02 3 68,383
147,523 40 0.06 57
0.04 4 81,815 229,338
62 0.08 119 0.05 5
105,821 335,159 80
0.08 199 0.06 6
127,028 462,187 78 0.06
277 0.06
Proportional report rate.
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Most Infliximab Associated Tuberculosis Occurs
Early in Tx
of Patients
PSUR 5 pg. 250. Baker et al. ACR 2001. PSUR 6
pg. 79.
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Algorithm for TB TestingEuropean-Based
Recommendations
New infliximab patient has office visit
Administer appropriate TB screening test (PPD
skin test chest x-ray family history)
Evaluate test results
PPD Test Positive and active TB
PPD Test Positive and normal CXR
Test Negative
Initiate latent TB treatment
Treat active TB to resolution
Initiate infliximab
Initiate infliximab
Initiate infliximab
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Serious Infusion Reactions Infliximab

ACCENT I through week 542
Proportion of Infusions with
Serious Infusion Reactions
Positive 1 / 254
Negative 3 / 656
Inconclusive 0 / 1470
Antibody-to-Infliximab Status
ATTRACT Study Report pg.288-289. ACCENT I Study
Report pg.262-263.
Patients with evaluable samples.
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New Management Trend In Crohns Diseases
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Inverting the Treatment Pyramid Step-Down
Therapy for CD
Early
Biologics (eg, infliximab)
Corticosteroids 5-ASA
AZA/6-MP/MTX
Surgery
Late
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The future Beginning Today ?
Surgery
Infliximab
Disease Severity
AZA/6-MP MTX
Prednisone Budesonide
5-ASA Antibiotics
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Chronically active CD
Surgery ?
Oui
Sequential management of steroid-dependent
patients

AZA or MTX
Failure (12 weeks)
Add Infliximab and maintain Q8 weeks
Reevaluation of Tx
(Dose escalation or reduce frequency)
Other Options