Preventing post-operative recurrence Dr Oliver Brain Oxford - PowerPoint PPT Presentation

Oxford Inflammatory Bowel Disease MasterClass Preventing post-operative recurrence Dr Oliver Brain Oxford

Disclosures  Presented at IEE, Oxford 2013 AbbVie sponsored meeting

Talk Outline  Risk factors for recurrence  Diagnosis of recurrence (briefly)  Evidence for recurrence prevention

Preventing post-op recurrence in CD  An important question  Goes to the heart of our understanding (or lack) of the biology of this disease  Recurrence in the absence of macro or microscopic disease  Why at the anastomosis? 1-3 1. Rutgeerts P et al Gut 1984;25:665-672. 2. Rutgeerts P et al Gastroenterology 1990;99:956-963. 3.Olaison G et al Gut 1992;33:331-335

Pre-OP Mucus DC T Cell Fibroblast Macrophage Paneth Cell

Post-OP Mucus DC DC Fibroblast Macrophage Paneth Cell T Cell

Crohn‟s phenotype over time Cosnes J et al Inflamm Bowel Dis 2002;8(4):244

Factors that may affect recurrence  Patient-related  Smoking (at least doubles recurrence rate) 1,2 *  Family history  Genetics  Disease-related  Age of onset*  Disease duration  Disease location – perianal disease 3 *  Disease behaviour – penetrating disease 4 *  Granulomas  Myenteric plexitis * ‘Reliable’ predictors  Surgery-related  Mutable  Prior resection 5 *  Potentially mutable  Extensive SB resection 5,6 *  Immutable  Resection margins  Anastomosis type  Strictureplasty  Laparoscopic vs open 1. Reese GE et al Int J Colorectal Dis 2008;23:1213-1221. 2. Ryan WR et al Am J Surg 2004;187:219-25 3. Hofer B et al Hepatogastoenterology 2001;48:152-5 4. Simillis et al Am J Gastroenterol 2008;103:196-205 5. Bernell O et al Br J Surg 2000;87:1697. 6. Welsch T et al Int J Colorectal Dis 2007;22:1043-9

Approach to Treatment Immediate Delayed No treatment • • • Disease behaviour Identifiable need No treatment risk Pros • • modification Known outcomes in Primum non nocere • Prevention of absence of treatment surgery / bowel length preservation • • • Ad hoc patient Limited data of Disease will almost Cons selection and disease modification invariably reoccur • ?overtreatment Disease morbidity • Ltd data of disease modification • When should we stop treatment?

Defining Recurrence  Clinical  Faecal / serum markers  Endoscopic  Capsule endoscopy  Radiological – MR, CT, US, SBE  Surgical

Defining Recurrence  Clinical – Symptoms, CDAI (or CRP) underestimate recurrence 1-3  Endoscopy – remains the gold standard  New lesions can be visualised within weeks to months  Mismatch / lag between endoscopic recurrence and symptoms  At 1 year 73% endoscopic vs 20% clinical 4 1. Viscido A et al Ital J Gastroenterol Hepatol 1999;31:274-279. 2. Regueiro et al Gastroenterology 2009;136:441-450e1. 3.Walters TD et al Inflamm Bowel Dis 2011;17:1547-1556. 4. Rutgeerts P et al Gut 1984;25:665-672

Crohn‟s disease recurrence - Endoscopic  Rutgeerts score 1 : i0 No lesions i1 ≤5 apthous lesions i2 >5, skip lesions, anastomotic lesions i3 Diffuse apthous ileitis i4 Diffuse with larger ulcers +/- narrowing Score POR risk 0-1 <10% at 10 yr 2 40% risk at 5 yr 3-4 50-100% risk at 5 yr 1. Rutgeerts P et al Gut 1984;25:665-672

Crohn‟s disease recurrence - Surgical The problem:  80% patients with Crohn’s disease require at least one resection 1  Surgery rates did not decline significantly in immunomodulator era 2  A small number of patients with CD develop short bowel syndrome  70% patients with CD require >1 resection over lifetime 3-5  15% surgical recurrence in 5 years 6 1. Caprili R et al Gut 2006;55(suppl 1):i36-58. 2. Cosnes J et al Gut 2005;54:237-241 3. Chardavoyne et ak Dis Colon Rectum 1986;29:495-502. 4. Lock et al NEJM 1981;304:1586-1588. 5. Landsend E et al Sand J Gastroenterol 2006;41:1204-1208. Peyrin-Biroulet L et al Am J Gastroenterol 2010;105:289-297

Medical therapies trialed  Antibiotics  5 ASA compounds  Steroids  Enteral nutrition  Probiotics  Immunomodulators  Anti-TNF agents  Other biologics

Imidazole Antibiotics  RCT metronidazole 20mg/kg/day vs placebo for 3 months 1  RCT ornidazole 1g/day vs placebo for 1 year 2  1 yr endoscopic recurrence RR 0.44 (95% CI 0.26-0.74) 3  1 yr clinical recurrence RR 0.23 (95% CI 0.09-0.57) 3  NNT 4 But:  Effect sustained only to 1 year  Higher rates adverse events RR 2.39 (95 CI 1.5-3.7) and withdrawal 1. D‘Haens GR et al Gastroenterology 2008;135:1123-1129. 2. Rutgeerts P et al Gastroenterology 2005;128:856-861. 3. Doherty GA et al Aliment Pharmacol Ther 2010;31:802-809

Budesonide  Two placebo-controlled trials of 3mg and 6mg / day 1,2  At 1 year post-op no improvement in:  Endoscopic recurrence  Clinical recurrence  In addition:  ½ patients on steroids post-op develop dependence or resistance at 1 year 3 1.Ewe K et al Eur J Gast Hep 1999;11:277-282. Hellers G et al Gastroenterology 1999;116:294-300. 3. Irving PM et al Aliment Pharmacol Ther 2007;26:313-329

5-ASA compounds  Mesalazine  3 x Meta-analyses:  Reduced post-op recurrence by 13% 1  No more effective than placebo 2  Decreased clinical but not endoscopic recurrence, and inferior to Aza/ 6-MP 3  Cochrane review 4  NNT 12 to prevent clinical recurrence  Sulfasalazine  No benefit demonstrated 4 1.Camma et al Gastroenterology 1997;113:1465-1473.2. Ford AC et al Am J Gastroenterol 2011;106:617-29 3. Doherty GA et al Gastroenterology 2009;136. 4. Doherty G et al Cochrane Data Sys Rev 2009:CD006873

Enteral Nutrition  Evaluated in a single prospective non-randomised study 1  40 pts, post-op ileal / ileo-caecal CD  20 pts self-administered nocturnal NG enteral feed  At 1 year: Control Enteral P value nutrition Clinical recurrence 35% 5% 0.048 Endoscopic recurrence 70% 30% 0.027  Unlikely to be widely applicable 1. Yamamoto T et al Aliment Pharmacol Ther 2007;25:67-72

Probiotics  Insufficient evidence of efficacy  Studies of: Lactobacillus johnsonii 1,2 Lactobacillus rhamnosus strain GG 3 Synbiotic 2000 4 VSL3 ♯ 5  Metanalysis found probiotics ineffective to prevent endoscopic or clinical recurrence 6 1. Marteau P et al Gut 2006;55:842-847. 2.Van Gossum A et al Inflamm Bowel Dis 2007;13:135-142. 3. Prantera C et al Gut 2002;51:385-389 4. Chermesh I et al Dig Dis Sci 2007;52:385-389. 5. Madsen K et al Gastroenterology 2008;134. 6. Doherty GA et al Aliment Pharmacol Ther 2010;31:802-809

Recombinant IL-10  One placebo-controlled trial 1  Tenovil given in 2 different regimens  37 Tenovil and 21 placebo patients had colonoscopy  At 12 weeks post-op no difference in:  Endoscopic recurrence  Clinical recurrence 1. Colombel JF et al Gut 2001;49:42-46

Thiopurines – Inflammation  Meta-analysis 1 (inc 4 RCTs)  Thiopurines more effective than control (placebo, antibiotics, 5ASA) at:  2 years: mean difference 13% (95% CI 2-24%); NNT 8 (clinical)  1 year: Prevents recurrence Rutgeerts i2-i4, but not severe i3-i4  Thiopurines more effective than placebo at:  1 year: mean difference 23% (95% CI 9-37%); NNT 4 (endoscopic) 1. Peyrin-Biroulet L et al Am J Gastroenterol 2009;104:2089-2096. 2. Ardizzone et al Gastroenterology 2004;127:730-740.

Thiopurines – Further Surgery  Retrospective review of 326 pts 1  46 pts required reoperation  > 3 years thiopurine  27% reoperation rate  < 3 months thiopurine  55% reoperation rate (p<0.004) Papay P et al Am J Gastroenterol 2010;105:1158

Anti-TNFs and Post-Op CD  Assumptions we might make:  Early instigation of treatment is better 1-4  Anti-TNF can maintain remission 5 (in responders)  Dual immunosuppression is better 6,7  We use anti-TNF in those with more severe disease 8  We can prevent further surgery  Longer duration of treatment is better 1. Hanauer S et al Lancet 2002;359:1541-1549. 2. Hymas J et al Gastroenterology 2007;132:863-873. 3. Peyrin-Biroulet L et al Gastroenterology 2008;135:1420- 1422. 4. Colombel J-F et al Gastroenterology 2007;132:52-65. 5. Behm BW et al Cochrane Rev 2008. 6. D‘Haens G et al Lancet 2008;371:660-7. Colombel et al NEJM 2010 ;362:1383-95

Early dual immunosuppression D‘Haens G et al Lancet 2008;371:660-7

Infliximab – Preventative Strategy  One published RCT 1  24 pts to IFX or placebo immediately post-op  IFX group: *more smokers 46% vs 8% *fewer immunomodulators 36% vs 54% Placebo Infliximab  At 1 year endo recurrence (i2-i4): 11/13 (85%) 1/11 (9%)  Other prospective open label trials 2-4 are small (total 33 IFX treated patients), but are largely reflective of this response 1. Regueiro et al Gastroenterology 2009;136:441-550. 2. Sorrentino et al 2007 Arch Intern Med 2007;167:1804. 3. Sakuraba et al Int J Colorectal Dis 2012;27:947. 4. Yoshida et al Inflamm Bowel Dis 2012;18:1617

Adalimumab – Preventative Strategy  Small prospective studies Study Control Patients Follow-up Outcome Response Rates 1 NA 8 2 yr Endoscopic 75% remission 2 NA 29 (high risk) 1 yr Endoscopic 79% remission High risk = 2 or more of: smokers, penetrating disease, extensive resection, ≥2 resections  Overall similar response rates to Infliximab 1. Papamichael et al J Crohn‘s Colitis 2012;6:924-931. 2. Aguas et al World J Gastroenterol 2012;18:4391-4398. 3.