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 Paneth Cell Macrophage Fibroblast
Post-OP Mucus DC DC Fibroblast Paneth Cell Macrophage T Cell
Cosnes J et al Inflamm Bowel Dis 2002;8(4):244 Crohn s phenotype over time
Factors that may affect recurrence Patient-related Smoking (at least doubles recurrence rate) 1,2 * Family history Genetics Disease-related Surgery-related Age of onset* Disease duration Disease location perianal disease 3 * Disease behaviour penetrating disease 4 * Granulomas Myenteric plexitis Prior resection 5 * Extensive SB resection 5,6 * Resection margins Anastomosis type Strictureplasty Laparoscopic vs open * Reliable predictors Mutable Potentially mutable Immutable 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 Pros Disease behaviour modification Prevention of surgery / bowel length preservation Cons Ad hoc patient selection and?overtreatment Ltd data of disease modification Identifiable need Known outcomes in absence of treatment Limited data of disease modification No treatment risk Primum non nocere Disease will almost invariably reoccur Disease morbidity 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 i1 i2 i3 i4 No lesions 5 apthous lesions >5, skip lesions, anastomotic lesions Diffuse apthous ileitis 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 nutrition P value 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
D Haens G et al Lancet 2008;371:660-7 Early dual immunosuppression
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% At 1 year endo recurrence (i2-i4): Placebo Infliximab 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 remission 2 NA 29 (high risk) 1 yr Endoscopic remission 75% 79% 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.
Anti-TNF agents Reactive strategy St u d y Drug Control Patie nts 1 Ifx 5ASA or Aza Time since surgery Follow-up Outcome Response rates 8 6 months 6 months Mucosal healing 38% 2 Ifx NA 6 1 year 1 year Endoscopic remission 50% 3 Ifx 5ASA 13 6 months 1 year Endoscopic remission 54% 4 Ifx or Ada NA 28 6 12 months NA Mucosal healing 50% 5 Ada NA 15 6 months 2 years Endoscopic remission 60% 1. Yamamoto et al 2009. 2 Regueiro et al 2010. 3 Sorrentino et al 2012. 4 Boueyre et al 2012. 5 Papamichal et al 2012.
Anti-TNF agents Reactive strategy St u d y Drug Control Patie nts 1 Ifx 5ASA or Aza Time since surgery Follow-up Outcome Response rates 8 6 months 6 months Mucosal healing 38% 2 Ifx NA 6 1 year 1 year Endoscopic remission 50% 3 Ifx 5ASA 13 6 months 1 year Endoscopic remission 54% 4 Ifx or Ada NA 28 6 12 months NA Mucosal healing 50% 5 Ada NA 15 6 months 2 years Endoscopic remission 60% 1. Yamamoto et al 2009. 2 Regueiro et al 2010. 3 Sorrentino et al 2012. 4 Boueyre et al 2012. 5 Papamichal et al 2012.
Anti-TNF High risk phenotype 11 patients with multiple operations ( 2). Median 4. 3 smokers, 9 perianal disease, 9 previous 6-MP IFX 5mg/kg started 2-4 weeks post-op, not randomised Clinical remission at 2 years: 60% Endoscopic remission at 2 years: 40% Sakuraba et al Int J Colorectal Dis 2012;27:947.
Anti-TNF or Thiopurine? -High risk pts Open-label pilot. Prospective, randomised 1. 22 patients high risk, post-ileocaecal resection After 1 year: Endoscopic recurrence Histological recurrence (severe) Infliximab Azathioprine P value 9% 40% 0.14 18% 80% 0.008 High risk = 2 or more of: age < 30 at diagnosis; penetrating disease; previous surgery. 1. Armuzzi et al JCC 2013 (Epub)
Anti-TNF Preventing further surgery? Pair-matched study 100 post-op patients who received IFX Matched by gender, Vienna classification, age at operation Median follow-up: IFX Control 36 months 51 months Surgical recurrence: IFX Control 3/100 34/100 HR 0.22 (95% CI 0.11-0.44) Araki T et al Surg Today 2013 Mar 6 (Epub)
How long should we treat? Small study, not controlled 1 12 patients in endoscopic and clinical remission after 3 years IFX therapy (post-op) Re-scoped 4 months later 10/12 (83%) developed endoscopic recurrence Re-introduction IFX at 3mg/kg restored response 1. Sorentino et al Clin Gastroenterol Hepatol 2010;8:591-599
Summary 1 Effective Therapies 5 ASA minimal efficacy Imidazole antibiotics Enteral nutrition } Tolerance problems / not widely applicable Thiopurines Most effective of non-biologic therapies Anti-TNF most effective, and?better if used early No data on dual immunosuppression in this setting
Summary 2 General Approach Start with a good surgeon Individualised approach Consider risk factors for severe disease Bowel length preservation Stop smoking Endoscopic follow-up 6-12 months No medication for low risk disease, colonoscopy 6-12 months Thiopurines for moderate risk disease / i2-?i3 disease Anti-TNF +/- thiopurines high risk disease / i3-4 disease
Examples of my approach Patient 1 Patient 2 Patient 3 26 yr old man 1 st presentation. Smoker Stenosing isolated TI disease. Ileo-caecal resection Stops smoking post-op 28 yr old woman CD diagnosed age 19 Non-smoker Age 21 Rt hemicolectomy for ileocaecal disease (stenosis) 5ASA 1 year post-op Ileal resection (stenosis) 34 yr old man CD diagnosed 29 Non-smoker Appendectomy age 27 Azathioprine for 4 years 30cm TI resection plus 6 SB strictureplasties At resection has enteroenteric fistula No treatment Colonoscopy 6 months Thiopurine Colonoscope 6-12 months Anti-TNF +/- thiopurine Colonoscope and MRI SB at 6-12 months year