1. Prof D BA SILK MD AGAF FRCP Imperial College London St Mary’s Campus
The Role of the Gastroenterologist in the long term management of inflammatory bowel disease
Prof D BA SILK MD AGAF FRCP
Imperial College London
St Mary’s Campus

2. Incidence and prevalence of UC & Crohns Disease
(per 100,000 annually)
6 – 15
4 - 10
Prevalence
(per 100,000 annually
80 – 150
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3. Hospitals serving 250,000 population will look after
New Patients
Old Patients UC 28
290
Crohns Disease 18
154
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4. Roles of Gastroenterology in Medical Management of IBD
Treatment of active UC
Maintenance of remission in UC
Treatment of active CD
Maintenance of remission in CD
Thiopurines
CRC surveillance
IBD and pregnancy
IBD and stress
IBD and life expectancy
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5. Medical Management of IBD
Achievement of Remission
Maintenance of Remission
23/10/2017

6. Medical Therapy for Active Ulcerative Colitis
5 ASA
Corticosteroids
Thiopurines
Calcineurin inhibitors (cyclosporin and tacrolimus)
Anti-TNF therapy
Other biological Agents
Probiotics
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7. Management of Ulcerative Colitis
Proctitis
Left sided proctocolitis
Extensive colitis
Severe active ulcerative colitis
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8. Management of Active Proctitis
Mesalazine 1G suppository
Mesalazine enemas
Mesalazine suppository/enema + oral 5ASA
Mesalazine enema + topical steroid enema
Oral prednisolone
Immunosuppressants
Biologics
23/10/2017

9. Management of Active Left Sided Colitis
Mesalazine enema
Oral 5ASA
Mesalazine + topical corticosteroid enema
Oral corticosteroids
IV corticosteroids
23/10/2017

10. Management of Active Extensive Colitis
Oral 5ASA
Oral corticosteroids
Mesalazine enemas
Mesalazine + topical corticosteroids
Thiopurines
Biologics
23/10/2017

11. Severe Active Ulcerative Colitis
Bloody diarrhoea > 6/day and any of the following
Tachycardia > 90 bpm
Fever > 37.8o C
Hb < 10.5 g/dl
ESR > 30 mm/h
Patients should be admitted under the care of a multidisciplinary team including
Specialist gastroenterologist
Specialist colorectal surgeon
Intravenous corticosteroids
Rescue therapy (ciclosporin, tacrolumis, infliximeb, considered early (day 3)
Management demands careful clinical judgement
After
Second European evidence based consensus in the diagnosis and management of ulcerative colitis part 2 Current Management. J Crohns and Colitis 2012; 6:
23/10/2017

12. Maintenance of Remission – Ulcerative Colitis
Oral 5 ASA therapy g/d
Topical 5 ASA g/wk
Combination of both
Thiopurines
Early or frequent relapse
Responders to ciclosporin
Responders to anti TNF agents
Anti – TNF therapy
Failure of thiopurines
E coli strain Nissle 1917
VSL # 3
23/10/2017

13. Comparison of Oral 5ASA Medications
Mesalazine pH sensitive polymer coating
5 ASA
Sulfasalazine
Sulfapyridine ASA
Balsalazide
4 aminobenzoyl- alanine ASA
Olsalazine
5 ASA ASA
Diazobond
23/10/2017

14. Formulation release characteristics of mesalazine preparations
Site of release
Asacol
400mg
Mesalazine
(released at pH >7)
Eudragit S coated tablets
Terminal ileum & colon
Ipocol
400 mg
(released at pH <7)
Eudragit S
Salofalk
250 mg
(released at pH >6)
Eudragit L
Mid to distal ileum & colon
23/10/2017

15. Balsalazide vs Mesalazine – Maintenance & Remission in UC
1.5g bd n = 49
Asacol
1.2 g/d n = 46
Relapse at 3/12
5/49 (10%)
13/46 (28%)
p < 0.05
Remission rates at 12 months
58% NS
After Green et al APT 1998; 12: 1207
23/10/2017

16. Gastrointestinal pH profiles in patients with acute pan-ulcerative colitis
Controls
(n = 7)
Acute Pan Colitis
No treatment
Proximal small bowel
Distal small bowel
Right colon
p < 0.02
After Raimundo, Evans, Rogers & Silk 1992
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17. Gastrointestinal pH profiles in patients with ulcerative colitis (in remission)
Sulphasalazine
(n = 6)
Asacol
Olsalazine
(n = 5)
Proximal small bowel
Distal small bowel
Right colon * * *
* p < 0.05 or less vs controls
In 5 or 21 tracings in UC patients (23.8%) luminal pH at 7.0 or greater was sustained for less than 30 mins.
After Raimundo, Evans, Rogers & Silk 1992
23/10/2017

18. Mesalazine non adherence in ulcerative colitis
Quiescent UC ( n = 99)
Patients Remaining in remission
Time (months)
12 m
24 m
Adherent 40
36 (90%)
32 (80%)
Non Adherent 59
32 (54%)
28 (48%)
p = 0.001
Non Adherent patients 5.5 greater risk of recurrence at 24 m
Data after Kane et al
Am J Med 2008; 114:
23/10/2017

19. Use of 5ASA associated with a lower risk of CRC
Effect of 5 ASA use on colorectal cancer (CRC) and dysplasia risk in UC
Use of 5ASA associated with a lower risk of CRC
Use of 5ASA associated with a lower risk of combined endpoint of CRC or dysplasia
Velayes et al 2005
Am J Gastro; 100:
23/10/2017

20. Medical Management of Crohns Disease
Glucocorticosteroids
Budesonide
5 ASA agents
Thiopurines
Biological agents
23/10/2017

21. Infliximab-based treatment strategy – The Sonic Trial
Patients moderate to severe Crohn’s disease
508
Aza 2.5 mg/kg/d + Placebo + infliximab Aza 2.5 mg/kg/d + Infliximab
Placebo infusions (0, 2, 6 then every 8 weeks) (0, 2, 6 then every 8 weeks)
30 weeks
50 weeks
End points – primary
Steroid free remission (CDA < 150)
Off steroids > 3 weeks
End points – secondary
Mucosal healing
23/10/2017

22. Steroid Free Clinical Remission
(26/52)
Azathioprine monotherapy
31%
p = 0.009
p < 0.001
Infliximab monotherapy
44%
p = 0.022
Infliximab + Azathioprine
57%
(50/52)
24%
35%
p = 0.028
46%
Results accentuated in patients with high CRP > 80 mg/l and mucosal lesions
After Colombel et al 2008, Sandborn et al 2009, Colombel et al 2009
23/10/2017

23. Duration of Thiopurine Therapy in IBD
23/10/2017
Frazer Orchard & Jewell. Gut 2002; 50:485

24. Duration of Thiopurine Therapy in IBD
Frazer Orchard & Jewell. Gut 2002; 50:485
23/10/2017

25. Problems with Thiopurines
Bone marrow suppression
Lymphoma
Solid tumours
Skin cancer
Hepatitis
Hypersensitivity reactions
23/10/2017

26. Colorectal cancer risk in IBD
Extent histologic inflammation + pseudopolyps
Duration of disease (> 10 yrs)
Long standing extensive colitis (> 10 years disease; > 50% colon affected)
PSC
Colonic strictures
Farrge et al. AGA Medical Position Statement
Gastroenterology 2010; 138: 738
23/10/2017

27. Surveillance Colonoscopy
Baseline in all patients before 8 yrs disease
Patients with proctitis or proctosigmoiditis not considered at risk for IBD related CRC
All other patients should commence surveillance colonoscopy 1 -2 yrs after base line examination
Frequency dependent upon presence of risk factors ( 1-3 yrs)
After AGA Medical Position Statement
Gastroenterology 2010; 138: 738
23/10/2017

28. Use of chemo-preventative agents to lower risk of CRC in IBD
Mesalazine >1.2 g/d reduces risk of CRC by 81%
p = 0.006
Eaden et al APT : 145
Thiopurines reduce risk of CRC & HGD
Beaugenie et al Gastroenterology 2013l 145: 166
? Effect of Biological Agents
23/10/2017

29. How “Fail-Safe” are the Recommendations?
Cancers et Sorrisque Associe aux Maladies
Inflammatory Intestinales en France (CESAME)
19,486 patients with IBD
38.6% of CRC or HGD developed before 10 yr disease duration
Beaugenie et al Gastroenterology 2013l 145: 166
23/10/2017

30. Treatment of IBD in Pregnancy
Majority of drugs used in IBD are safe in pregnancy
Proactive treatment for maintenance of remission advised
Active disease and not therapy pose the greatest risk to the pregnancy
Caprille et al Gut 2006;55 (suppl 1): 36-58
23/10/2017

31. Significantly reduces
Effect of Disease Activity and Treatment of disease on Fertility in Males and Females with IBD
Effect on Fertility
Inflammatory Bowel Disease/Treatment Type
Male
Female
Active Disease
No effect
Reduces
Sulphasalazine
Significantly reduces
5-Aminosalicylic Acid
Corticosteroids
Mercaptopurine/Azathioprine
Biological Agents
Unlikely
Small/large bowel resection
Ileal pouch anal anastomosis
After Heetun et al AP & T 2007; 26:
23/10/2017

32. Effect of Gestation on Course of IBD
% of patients in remission during pregnancy
% of patients with worsening chronically active disease during pregnancy UC CD
Disease in remission at conception
70 – 80%
70%
20 – 30%
30%
Active disease at conception
33%
50 – 70%
67%
After Heetun et al AP & T 2007; 26:
23/10/2017

33. Effect of ulcerative colitis and Crohn’s disease on rates of preterm delivery and low birth weight compared to the general population
Outcome
Ref
No of Patients
UC adjusted odds ratio
CD adjusted odds ratio
Preterm delivery
(< 37 weeks) 1 2 3
10565
1570
3528
1.2 ( )
1.01 (0.40 – 2.52)
2.31 ( )
2.4 ( )
Low Birth weight (<2500g)
10598
0.8 ( )
1.13 (0.38 – 3.35)
3.62 ( )
1.6 (1.1 – 2.3)
Norgard et al Am J Gastroenterol. 2000; 95:
Domintz et al Am J Gastroenterol. 2002; 97: 641 – 648
Fonager et al Am J Gastroenterol. 1998; 93:
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34. Effects of stress on inflammation in IBD mediated through changes in
Chronic stress, adverse life events and depression can cause relapse in patients with IBD
Bitton et al Am J Gastro 2003; 98: 2203
Mardini et al Dig Dis Sci 2004; 49: 492
Levenstein et al Am J Gastro 2000; 95: 1213
Effects of stress on inflammation in IBD mediated through changes in
Hypothalamic-pituitary-adrenal function
Bacterial-mucosal flora interactions
Activation of mucosal mast cells
Peripheral release of CRF
Symptoms of IBD exacerbated by effects of stress
Gut motility
Fluid secretion
After Mandsky & Rampton Gut 2005; 54: 481
23/10/2017

35. Predicting Relapse in Crohn’s Disease
101 Patients in Remission
14 Withdrew Relapsed
Risk Factors for Flare Up
p value
CRP
Fistulising Disease
Colitis
Perceived stress
Low levels of stress and low avoidance behaviour had sustained remission (85% at 1 yr)
After Bitton et al Gut 2008; 17: 1386
23/10/2017

36. Influence of Ulcerative Colitis in Life ExpectancyNo
Reference
Findings 1
Stonnington et al
Gut 1987; 28:
“Overall survival was similar to that expected for the general population at like age and sex” 2
Ekbom et al
Gastro 1992; 103:
Pan colitis of 10 years standing, the relative survival rate was 92.8% compared to general population 3
Probert et al
Dig. Dis. Sci. 1993;38:
Overall mortality not increased including pan colitis 4
Persson et al
Gastro 1996; 110:
In UC standardised mortality rate was Authors conclude “slightly increased mortality in ulcerative colitis” 5
Palli et al
Gut 1998; 42:
“General mortality was significantly lower than expected in patients with ulcerative colitis”. 6
Loftus et al
Gut 2000; 46:
Overall survival similar to that of general population 7
Farrokhyar et al
Am J Gastro 2001; 96:
“Mortality rates are not increased in IBD compared with the general population” 8
Gastro2003; 125:
Life expectancy in females aged less than 50 years with ulcerative colitis normal
23/10/2017

37. Multidisciplinary, patient focused IBD Clinics in Secondary Care
Consultant Gastroenterologist
Clinical Nurse Specialist
Dietitian
Clinical Psychologist
Silk 2013
23/10/2017