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

Incidence and prevalence of UC & Crohns Disease (per 100,000 annually) 6 – 15 4 - 10 Prevalence (per 100,000 annually 80 – 150 27 - 106 23/10/2017

Hospitals serving 250,000 population will look after New Patients Old Patients UC 28 290 Crohns Disease 18 154 23/10/2017

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 23/10/2017

Medical Management of IBD Achievement of Remission Maintenance of Remission 23/10/2017

Medical Therapy for Active Ulcerative Colitis 5 ASA Corticosteroids Thiopurines Calcineurin inhibitors (cyclosporin and tacrolimus) Anti-TNF therapy Other biological Agents Probiotics 23/10/2017

Management of Ulcerative Colitis Proctitis Left sided proctocolitis Extensive colitis Severe active ulcerative colitis 23/10/2017

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

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

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

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: 991-1030 23/10/2017

Maintenance of Remission – Ulcerative Colitis Oral 5 ASA therapy 2.4 g/d Topical 5 ASA 3.0 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

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

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

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

Gastrointestinal pH profiles in patients with acute pan-ulcerative colitis Controls (n = 7) Acute Pan Colitis No treatment Proximal small bowel 6.6 + 0.5 6.1 + 0.8 Distal small bowel 7.4 + 0.4 7.2 + 0.5 Right colon 6.7 + 0.3 4.7 + 0.7 p < 0.02 After Raimundo, Evans, Rogers & Silk 1992 23/10/2017

Gastrointestinal pH profiles in patients with ulcerative colitis (in remission) Sulphasalazine (n = 6) Asacol Olsalazine (n = 5) Proximal small bowel 6.0 + 0.8 6.6 + 01.2 5.9 + 0.6 Distal small bowel 7.0 + 1.0 7.4 + 1.2 7.0 + 0.3 Right colon 4.9 + 1.3* 5.5 + 1.1* 5.5 + 0.4* * 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

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: 39 - 43 23/10/2017

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: 1345 - 1353 23/10/2017

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

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

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

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

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

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

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

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

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 2000 14: 145 Thiopurines reduce risk of CRC & HGD Beaugenie et al Gastroenterology 2013l 145: 166 ? Effect of Biological Agents 23/10/2017

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

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

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: 513-533 23/10/2017

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: 513-533 23/10/2017

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 (0.9 - 1.5) 1.01 (0.40 – 2.52) 2.31 (1.41 - 3.77) 2.4 (1.6 - 3.7) Low Birth weight (<2500g) 10598 0.8 (0.6 -1.2) 1.13 (0.38 – 3.35) 3.62 (2.22 - 5.88) 1.6 (1.1 – 2.3) Norgard et al Am J Gastroenterol. 2000; 95: 1165 -1170 Domintz et al Am J Gastroenterol. 2002; 97: 641 – 648 Fonager et al Am J Gastroenterol. 1998; 93: 2426 - 2430 23/10/2017

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

Predicting Relapse in Crohn’s Disease 101 Patients in Remission 14 Withdrew 37 Relapsed Risk Factors for Flare Up p value CRP 0.007 Fistulising Disease 0.04 Colitis 0.02 Perceived stress 0.0006 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

Influence of Ulcerative Colitis in Life Expectancy No Reference Findings 1 Stonnington et al Gut 1987; 28: 1261-1266 “Overall survival was similar to that expected for the general population at like age and sex” 2 Ekbom et al Gastro 1992; 103: 954-960 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: 538-541 Overall mortality not increased including pan colitis 4 Persson et al Gastro 1996; 110: 1339-1345 In UC standardised mortality rate was 1.37. Authors conclude “slightly increased mortality in ulcerative colitis” 5 Palli et al Gut 1998; 42: 175-179 “General mortality was significantly lower than expected in patients with ulcerative colitis”. 6 Loftus et al Gut 2000; 46: 336-343 Overall survival similar to that of general population 7 Farrokhyar et al Am J Gastro 2001; 96: 501-507 “Mortality rates are not increased in IBD compared with the general population” 8 Gastro2003; 125: 1576-1582 Life expectancy in females aged less than 50 years with ulcerative colitis normal 23/10/2017

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