1. Rahul A. Nathwani, MD, FACG
7th Middle East Gastroenterology and Hepatology Conference April 13th, 2012
“Crohns disease: Are new Rx guideline algorithms applicable to patients from our area ?”
Rahul A. Nathwani, MD, FACG
American Board Certified in Internal Medicine
American Board Certified in Gastroenterology
Consultant Gastroenterologist & Hepatologist
Dubai Healthcare City

2. Evolution of Therapeutic Goals
10 years ago…
What has changed today
Symptomatic remission
Improve quality of life
Induction use then treat on flare
Reduce steroid use
Timely drug intervention
Long-term sustainability (scheduled maintenance)
Maintain steroid-free remission
Complete mucosal healing
Reduction in long-term implications of chronic disease
Deep remission
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 68/ Golimumab-Specific Deck: No

7. Predictors of Disabling CD
Steroid Requirement
Age <40
Perianal Disease 1 2 3 4 5
Independent factors at diagnosis
Odds ratio
2.1
1.8
3.1
P=0.0004
P=0.01
P=0.0001
Retrospective derivation cohort
1123 patients
Prospective validation cohort
302 patients
Definition disabling (any)
≥2 steroid courses
Steroid dependence
Hospitalisation
Chronic (>12 mo) symptoms
Need immunosuppressants
Need surgery
Beaugerie & cols, took a different approach to identify at diagnosis factors predictive of a subsequent 5-year disabling course
The authors defined “disabling disease” as the presence of at least 1 of the criteria of clinical severity was present.
The estimate the prevalence of disabling disease they limited the analysis to a retrospective group of 262 individuals diagnosed and followed in their unit. In these patients the estimation bases on a best and worse scenario of disabling disease in patients LTFU was %.
Among the 1123 patients with follow-up data allowing full 5-year course classification, the rate of disabling disease was 85.2%. Independent factors resent at diagnosis and significantly associated with subsequent 5-year disabling were the initial requirement for steroid use (OR 3.1 [95% CI: 2.2– 4.4]), an age below 40 years (OR 2.1 [95% CI: 1.3–3.6]), and the presence of perianal disease (OR 1.8 [95% CI: 1.2–2.8]). The positive predictive value of disabling disease in patients with 2 and 3 predictive factors of disabling disease was 0.91 and 0.93, respectively. These values were 0.84 and 0.91, respectively, when tested prospectively in an independent group of 302 consecutive patients seen at our institution from 1998.
However, these values have to be put into perspective relative to the proportion of patients with disabling disease. In the derivation cohort prevalence of disabling disease was 85%. Therefore, tossing a coin would have a predictive value of .85, and the prevalence of disabling disease in the validation cohort is not clarified in the manuscript.
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 21/ Golimumab-Specific Deck: No
Beaugerie L, et al. Gastroenterology. 2006;130:

8. More Than 2 Risk Factors Predict a Disabling Disease Course in CD
Score 0 (0 Factors of Disabling Disease)
Score 1 (1 Factor)
Score 2 (2 Factors)
Score 3 (3 Factors)
100 93 91 90 80 67 70 61 60 51
Percentage (%) 50 40 31
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 22/ Golimumab-Specific Deck: No 30 20 13 5 10
Distribution
Positive Predictive Value
N=1123
Beaugerie L, et al. Gastroenterology. 2006;130:

9. Patient Case 29-year-old female, lawyer Smoker February 2009
Bloody diarrhea (4–6 liquid stools/day)
Weight loss (10%) and abdominal pain (moderate)
General well-being: poor
No ulceration or fistula on perianal exam
Blood tests
Haemoglobin 9.7 mg/dL, hematocrit 28%
Platelet count 540x106
ESR 63 mm/h, CRP 41 mg/L
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 28/ Golimumab-Specific Deck: No

10. Crohn’s Disease (CD) Diagnosis
Colonoscopy
Aphtous and superficial ulcers in the terminal ileum and whole colon
Deep ulcers in the low rectum
Histology: Granuloma
MRI: 50 cm small
Bowel involvement in the terminal ileum
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 29/ Golimumab-Specific Deck: No

11. Ileum Sigmoid Transverse colon Rectum 11
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 51/ Golimumab-Specific Deck: No 11

12. Risk Factors for Progressive Disease in Luminal CD
Terminal ileal location1
Young
Smoker2,3
Severe endoscopic lesions8
Lawyer
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 31/ Golimumab-Specific Deck: No
1Solberg IC, et al. Clin Gastroenterol Hepatol. 2007;5: ; 2Sutherland LR, et al. Gastroenterology. 1990;98: ; 3Lindberg E, et al. Gut. 1992;33: ; 4Reese GE, et al. Am J Gastroenterol. 2006;101: ; 5Gearry RB, et al. Inflamm Bowel Dis. 2007;13: ; 6Armuzzi A, et al. Gut. 2003;52: ; 7Boirivant M, et al. J Clin Gastroenterol. 1988;10: ;8Allez M, et al. Am J Gastroenterol. 2002;97: 12

13. Clinical question ? What Rx should this pt receive ?
5 ASA + steroid
5 ASA + steroid + AZA introduced during the 2nd course of steroids
Steroid + AZA
Biologic therapy

14. Patient Case (Cont.)
Patient treated with oral steroids at the dose of 1 mg/kg/day and AZA 2.5 mg/kg/day
Patient was clinically well
Blood tests 1 month after: Hb 11.5 mg/L, CRP 0.7 mg/L, ESR 25 mm/h, platelet count 390x106
Steroids tapered (5 mg/week)
After 4–5 weeks of steroid discontinuation, disease relapsed
Again diarrhea, blood, abdominal pain
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 36/ Golimumab-Specific Deck: No

15. Patient Case (Cont.) Anti-TNF therapy started AZA continued
Symptom-free after 4 weeks
Blood tests: Hb 12.5 mg/L, CRP 0.3 mg/L
At the moment in steroid-free remission
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 43/ Golimumab-Specific Deck: No

16. Endoscopy: Complete Mucosal Healing
Patient Case (Cont.)
Endoscopy: Complete Mucosal Healing
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 44/ Golimumab-Specific Deck: No

17. The Evolution of Therapy: Toward Optimal Treatment of CD
Sequential step-up approach
Accelerated step-up approach
5-ASA
Antibiotics
Prednisone
Anti-TNF
Surgery
AZA/6-MP
Budesonide
MTX
Prednisone
Budesonide
MTX
Anti-TNF
and AZA/6-MP
Surgery? 17

18. Limitations for Conventional Therapy
Steroids
Complications of prolonged steroid exposure
Relapse off steroids is high and will require maintenance treatment (immunosuppressant)
Azathioprine (AZA)
Slow onset of action of AZA may preclude its use for active disease1
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 33/ Golimumab-Specific Deck: No
1Dignass A, et al. J Crohn’s Colitis. 2010;4:28-62.

19. The Evolution of Therapy: Accelerating Steps in CD Treatment
Disability
Complications
Anti-TNF
Infliximab or adalimumab
Disease Progression
MTX
Disease Control
Prednisone
Budesonide
and AZA/6-MP 19

20. Advancing Outcomes in CD
5-ASA
Antibiotics
Prednisone
Anti-TNF
Surgery
AZA/6-MP
Budesonide
MTX
Evolving approach
Classical approach
Panaccione R, et al. Aliment Pharmacol Ther. 2008;28 :

21. Step Up vs Top Down Therapy
D’Haens etal. Lancet 2008;371:

22. Clinical Remission Without Corticosteroids at Week 26
SONIC
Clinical Remission Without Corticosteroids at Week 26
Primary End Point
100
P<0.001 80
P=0.009
P=0.022
56.8 60
Proportion of Patients (%)
44.4 40
30.6
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########## Presentation updated on Tuesday, 2 March, 2010 by SILE ##########
########## Presentation updated on Friday, 20 February, 2009 by WEBO ##########
########### Presentation updated on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 55/ Golimumab-Specific Deck: No
########### Presentation 'SONIC ACGabstract Deck_10OCT2008 .ppt' created on Friday, 10 October, 2008 ###########
Author: MedAdv QC&C: 10-Oct Review By: 10-Mar-09
Medical Review: No Slide: 10/15 20
52/170
75/169
96/169
AZA + placebo
IFX + Placebo
IFX+ AZA
Colombel JF, et al. J Crohn’s Colitis. 2009;3(1):S45-46; Data on File. Centocor, Inc.

23. Mucosal Healing at Week 26
SONIC
Mucosal Healing at Week 26
100
Secondary End Point
P<0.001 80
P=0.023
P=0.055 60
Proportion of Patients (%) 44
At week 26, more patients experienced complete mucosal healing while receiving infliximab monotherapy (30%; P=0.023) and infliximab-plus-AZA combination therapy (44%; P<0.001) than AZA monotherapy (17%). There was no significant difference between the 2 infliximab groups (P=0.055).
Reference
Colombel JF, Rutgeerts P, Reinisch W, et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. J Crohn’s Colitis. 2009;3:S45-S46.
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 56/ Golimumab-Specific Deck: No 40 30 17 20
18/109
28/93
47/107
AZA + Placebo
IFX + Placebo
IFX + AZA
Colombel JF, et al. J Crohn’s Colitis. 2009;3:S45-S46; Data on file. Centocor, Inc.

26. Natural Course of Crohns Disease
Effective
therapy
Loss of bowel function

27. Evidence-based CD Treatment Algorithm
Surgical interventions
Anti-TNF+ AZA/ 6-MP
AND/OR
Complex Fistulising Disease
After 6-12 months with stable remission†, stepping down to Anti_TNF monotherapy may be an option for some patients
Delayed (> 6 months)
Remission
Taper to AZA monotherapy
Relapse
Early (<6 months)
Steroids Plus AZA/6-MP
No Remission
CD Diagnosis
Anti-TNF+/- AZA/6-MP
Luminal CD with Risk Factors
Risk factors can include:
Smoker
Extensive disease (>40cm ileal disease)
Deep ulcerations
Systemically unwell (hemoglobin, albumin, Weight loss)
High “gut” damage (multiple surgeries [≥2])
Steroid dependence
Disease location (gastro duodenal, rectal, perianal)
Elevated CRP
Serological markers
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 46/ Golimumab-Specific Deck: No
Luminal CD
† Normal CRP, steroid-free clinical remission with mucosal healing.

28. Evidence-based CD Treatment Algorithm
IFX Evidence-based CD Treatment Algorithm
Evidence-based CD Treatment Algorithm
IFX + AZA/ 6-MP
AND/OR
Complex Fistulising Disease
Surgical interventions
No Remission
After 6-12 months with stable remission, stepping down to Anti-TNF monotherapy may be an option for some patients
Anti-TNF +/- AZA/6 MP
Risk factors can include:
Smoker
Extensive disease (>40cm ileal disease)
Deep ulcerations
Systemically unwell (hemoglobin, albumin, Weight loss)
High “gut” damage (multiple surgeries [≥2])
Steroid dependence
Disease location (gastro duodenal, rectal, perianal)
Elevated CRP
Serological markers
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 47/ Golimumab-Specific Deck: No
† Normal CRP, steroid-free clinical remission with mucosal healing.
†Normal CRP, steroid-free clinical remission with mucosal healing. 28

29. Evidence-based CD Treatment Algorithm
Surgical interventions
Anti-TNF + AZA/ 6-MP
AND/OR
Complex Fistulising Disease
CD Diagnosis
Luminal CD With Risk Factors*
Risk factors can include:
Smoker
Extensive disease (>40cm ileal disease)
Deep ulcerations
Systemically unwell (hemoglobin, albumin, Weight loss)
High “gut” damage (multiple surgeries [≥2])
Steroid dependence
Disease location (gastro duodenal, rectal, perianal)
Elevated CRP
Serological markers
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 24/ Golimumab-Specific Deck: No
Luminal CD

30. IFX Evidence-based CD Treatment Algorithm
Complex Fistulising Disease
Surgical interventions
Ant-TNF+ AZA/ 6-MP
AND/OR
Anti-TNF + AZA/6MP
And/or
Surgical ___interventions
CD Diagnosis
Luminal CD with Risk Factors*
Risk factors can include:
Smoker
Extensive disease (>40cm ileal disease)
Deep ulcerations
Systemically unwell (hemoglobin, albumin, Weight loss)
High “gut” damage (multiple surgeries [≥2])
Steroid dependence
Disease location (gastro duodenal, rectal, perianal)
Elevated CRP
Serological markers
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 25/ Golimumab-Specific Deck: No
Luminal CD 30

31. Fistula Response at Week 54
ACCENT II
Fistula Response at Week 54
Responders
P=0.001
P=0.009
23/98
42/91
19/98
33/91
Sands BE, et al. N Engl J Med. 2004; 350:

32. Effect of Infliximab on Hospitalisations in Fistulising CD
ACCENT II
Effect of Infliximab on Hospitalisations in Fistulising CD
Responders
Proportion of patients hospitalised
P<0.05
P<0.05
Page 865, Figure 3
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 18/ Golimumab-Specific Deck: No
All Randomised Patients
Week 14 Responders
Lichtenstein GR, et al. Gastroenterology. 2005;128:

33. Effect of Infliximab on Surgeries in Fistulising CD
ACCENT II
Effect of Infliximab on Surgeries in Fistulising CD
Responders
Most frequent surgeries
Resection of the bowel
Fistula-related surgeries
Ostomy placement or revision
Cumulative number of surgeries
P<0.05
Page 865, Figure 3
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 19/ Golimumab-Specific Deck: No
Lichtenstein GR, et al. Gastroenterology. 2005;128:

36. Natural history of Crohns disease
80% of Crohns disease patients will require surgery during their lifetime
Of these 70% will go on to a further operation

47. Factors determining applicability to our patients
Incidence
Diversity of pt population
Natural history of the disease
Patient compliance
Insurance related issues

48. The global map of inflammatory bowel disease

49. Factors determining applicability to our patients
Incidence
Diversity of pt population
Natural history of the disease
Patient compliance
Insurance related issues

50. Proportion of patients with colectomy through 54 weeks
ACT 1 & ACT 2
Proportion of patients with colectomy through 54 weeks
p=0.035
Why are the results significant in ACT II only: the proportion of placebo patients who received commercial remicade as a a rescue therapy was higher than that for combined-infliximab patients in ACT 1, but similar in ACT II. This may have counfounded the outcome in ACT 1.
There was a strong positivie trend for the 5mg/kg dose. The 5mg and 10mg group separately wre not powered to show a statistically significant difference. The discrepancy in patients receiving commercial Remicade in different subgroups is also important here.
n=36/244
n=46/484
Sandborn et al. UEGW 2007 Abstract OP-G-115. Data on file, Centocor

51. Factors determining applicability to our patients
Incidence
Diversity of pt population
Natural history of the disease
Patient compliance
Insurance related issues

52. Summary Treat beyond symptom control to achieve deep remission
Risk stratify patients early in disease and identify patients with poor prognosis early
Patients with luminal disease + risk factors
May benefit from accelerating through the treatment algorithm to receive biologic therapy
Consider top hold to biologics
Biologic therapy +/- immunomodulator therapy first line for fistulizing disease
Early treatment may alter disease progression and lead to improved outcomes
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 45/ Golimumab-Specific Deck: No

53. Summary Ileostomy is a protective factor for post-op recurrence
Colonoscopy at 12 months is procedure of choice to diagnose post-op recurrence
Apthous ulcers in the neo-terminal ileum is the earliest endoscopic lesion predictive of recurrence
Risk stratify in post-op setting as well
- Metronidazole in all pts for 3 months (if pt can tolerate)
- Immunomodulator therapy is modestly effective
- Use biologics for pts at high risk for disease recurrence
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 64/ Golimumab-Specific Deck: No

54. Summary
Incidence of Crohn’s in the Middle East is low but rapidly increasing
Diversity of population, aggressiveness of disease progression, pt compliance and insurance approvals may affect implementation of Rx guidelines in our pts
Tailor Rx based on each individual pts disease
Emirates Society of Gastroenterology should develop consensus guidelines in keeping with our pts disease spectrum
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'MSD ECCO Symposium slides FINAL.ppt' created on Tuesday, 2 March, 2010 ###########
Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A
Review Type: Local MSD Review req'd Slide: 64/ Golimumab-Specific Deck: No