Mucosal healing: does it really matter? Professor Jean-Frdric - PowerPoint PPT Presentation

Oxford Inflammatory Bowel Disease MasterClass Mucosal healing: does it really matter? Professor Jean-Frédéric Colombel, New York, USA

Oxford Inflammatory Bowel Disease MasterClass Mucosal healing: does it really matter ? Jean-Frederic COLOMBEL Icahn Medical School at Mount Sinai, New York

D.Rumsfeld

• In UC, mucosal healing is associated with better outcomes • The degree of healing influences the outcomes UC = ulcerative colitis

UC: outcomes at 5-year follow-up according to early response to steroids 100 Clinical and endoscopic remission Clinical no endoscopic remission # 80 No remission * 60 # # * 40 * 20 * 0 Relapse Hospitalisation Immuno- Colectomy suppression *p<0.05 vs clinical and endoscopic remission # p<0.05 vs clinical remission (± endoscopic remission) Ardizzone S, et al. Clin Gastroenterol Hepatol 2011;9:483 – 9

ACT 1 and ACT 2 UC: Early Mucosal Healing With Infliximab is Associated With Improved Long-term Clinical Outcomes Infliximab-treated patients P <0.0001 Patients, % Week 8 endoscopic score Colombel JF et al. Gastroenterology. 2011 Jun 29. [Epub ahead of print]. Colombel JF, et al. Gastroenterology 2011;141:1194 – 201

ACT 1 and ACT 2 UC: Early mucosal healing with infliximab is associated with reduced risk of colectomy Kaplan-Meier Estimates of Time to Colectomy in Infliximab-Treated Patients p value b Week 8 endoscopy No. of Week 54 colectomy-free score (n=466 a ) colectomies probability (%) (log rank) 0 (n=120) 6 95 0.0004 1 (n=175) 8 95 2 (n=114) 14 87 3 (n=57) 10 80 a Patients randomised to infliximab. Patients who had colectomy or discontinued before week 8 were not included b p value indicates the difference in distributions of time to colectomy among the 4 endoscopy score subgroups UC = ulcerative colitis Colombel JF, et al. Gastroenterology 2011;141:1194 – 201

UC: Early mucosal healing with infliximab is associated with reduced risk of infliximab failure Survival without IFX failure according to the initial endoscopic response to IFX Laharie D , et al. Aliment Pharmacol Ther 2013;37:998 – 1004

• In CD mucosal healing is associated with better outcomes • The relationship between the degree of endoscopic healing and outcomes – is not yet established – may be influenced by treatments CD = Crohn’s disease

CD: Early mucosal healing is associated with long-term remission (Extend) Among patients treated with anti-TNF, the best endoscopic response a w12 is associated to highest chances of clinical remission at 1 year (CDAI<150 alla w52) p<0.0001 OR 19.6 (95%CI 4.79-80.2) 100% 90% Remission 75% Activity 68% 50% 32% 25% 10% 0% 21/31 10/31 3/31 28/31 SES-CD<5 SES-CD>5 Sandborn WJ , et al. Gastroenterology 2012;142:1102-1111.

CD: Endoscopic healing in CD at year 2 predicts sustained clinical remission (SUTD) 49 patients from SUTD trial underwent colonoscopy at year 2 and were followed-up through year 3 and 4 100% Patients in remission years 3-4 p=0.036 p=0.032 OR=6.48 OR=7.5 (95%CI 1.8-23.4) 75% (95%CI 1.9-29.3) p=0.009 (%) 50% OR=0.148 (95%CI 0.016-1.38) 25% 0% Remission off-GCS & off- New or active draining Remission off-GCS IFX fistulae SES-CD = 0 (n=24) 71% 63% 4% SES-CD 1-9 (n=22) 27% 18% 23% Baert F, et al. Gastroenterology 2010; 138(2):463-8

CD: mucosal healing at one year is associated with a reduced risk of surgery IBSEN study: risk of future surgery in patients with mucosal healing at 1 year (n=146) 1.0 Proportion of patients Mucosal healing 0.9 not resected 83% 0.8 0.7 No mucosal healing 69% 0.6 Hazard ratio = 0.42, 95% CI 0.20 – 0.89; p=0.027 0.5 Adjusted for age and disease extent at diagnosis 0 1 2 3 4 5 6 7 8 9 Time after 1-year visit (years) Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430 – 8

CD: patients who achieved deep remission * with adalimumab at Week 12 were less hospitalized through week 52 (Extend) All-cause hospitalisation CD-related hospitalisation through Week 52 through Week 52 CD-related hospitalisation (%) 20 20 17 All hospitalisation (%) 15 15 9 10 10 5 5 0/11 9/53 0/11 5/53 0 0 Deep Non-deep Deep Non-deep remission * remission * remission * remission * (Week 12) (Week 12) (Week 12) (Week 12) * Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND Colombel JF , et al. Clin Gastroenterol Hepatol, 2013.

CD: patients who achieved deep remission * with adalimumab at Week 12 had better quality of life through wek 52 (Extend) IBDQ remission † at Week 52 p <0.05 75 64 IBDQ remission † (%) Patients in 50 26 25 14/53 7/11 0 Deep remission * Non-deep remission * (Week 12) (Week 12) * Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND † IBDQ remission defined as IBDQ score ≥170 Colombel JF , et al. Clin Gastroenterol Hepatol, 2013.

• In CD mucosal healing is one of the predictors of relapse after anti-TNF withdrawal • Mucosal healing does not predict relapse after corticosteroid or azathioprine withdrawal TNF = tumour necrosis factor

Relapse upon infliximab discontinuation (STORI) Treated with combined scheduled infliximab+immunosuppressive therapy for at ≥1 year In stable remission without steroid for >6 months Factors predicting time to relapse: male gender, surgery, steroids, Hb, WBC, hsCRP, CDEIS Global and individual curves according to predictive index 1.0 Index # relapse 0.8 ≤ 4 2/19 Proportion =5 10/36 0.6 Global 40/107 0.4 =6 13/24 0.2 =7 25/28 0.0 0 3 6 9 12 15 18 21 24 27 30 33 Time since inclusion (months) # at risk: 115 102 79 63 51 47 39 27 20 12 9 HsCRP = high-sensitivity C-reactive protein; CDEIS = CD endoscopic index of severity Louis E, et al. Gastroenterology 2012;142:63-70.

Relapse after steroid withdrawal according to endoscopic remission Prospective study in active colonic or ileocolonic CD patients (n=147), treated with prednisolone 1 mg/kg/d. Endoscopic evaluation of those who entered in clinical remission (92%) after 3 – 7 weeks of treatment, and follow-up for 18 months or until relapse Maintained clinical remission on follow-up 100 Endoscopic remission (n=33) 80 60 40 NO initial endoscopic remission (n=37) 20 0 0 2 4 6 8 10 12 14 16 18 Landi B, et al. Gastroenterology 1992;102:1647 – 53

Randomised, double-blind, placebo-controlled, multicentre azathioprine withdrawal trial in CD 1.0 Presence of 0.8 Remission rate endoscopic lesions (CDEIS 0) or 0.6 Azathioprine ulcerations was Placebo 0.4 not a predictor 0.2 of relapse 0.0 0 6 12 18 Time after randomisation (months) Patients 40 38 (1) 34 (2) 23 (3) Azathioprine at risk 43 40 (3) 35 (7) 27 (9) Placebo (relapses): Lémann M, et al, Gastroenterology 2005;128:1812 – 8

D.Rumsfeld

What is the definition of mucosal healing ? Ulcerative colitis Crohn’s disease • Normal, improved, no change or • No mucosal ulceration in any of 5 worse segments • Severity of bleeding without • Absence of mucosal ulceration considering ulcers • Disappearance of all ulcerative • UC- DAI≤1 lesions • Mayo≤ 1 • CDEIS ≤2, ≤3, ≤4, ≤6 • UCEIS < ? • SES- CD ≤5 • Rutgeerts score ≤i1 Need for homogenous definition of endoscopic healing

What is the prognostic endoscopic threshold in CD? 38.4 Need for major abdominal 40 30 surgeries 20 14.1 14.0 10 n=12 n=6 n=12 0 Complete Partial mucosal No mucosal mucosal healing healing healing (n=85) (n=43) (n=86) Schnitzler F, et al. Inflamm Bowel Dis 2009;15:1295 – 301

Endoscopic response at wk 26 predicts corticoid-free remission at wk 50 (SONIC) Roc Curve for detecting corticoid-free remission Roc Curve for detecting corticoid-free remission at wk 50 using the SES-CD % reduction from at wk 50 using the CDEIS % reduction from baseline to wk 26 baseline to wk 26 Mucosal healing and endoscopic response (defined as a decrease from baseline in SESCD or CDEIS of at least 50%) at week 26 identified patients most likely to be in CFREM at week 50 Ferrante M , et al. Gastroenterology; in press.

Mucosal healing and the small bowel ? Before therapy Calabrese C, et al. Aliment Pharmacol Ther 2008;27:759 – 64

Mucosal healing and the small bowel ? After therapy Calabrese C, et al. Aliment Pharmacol Ther 2008;27:759 – 64

UC: is rectosigmoidoscopy enough to assess mucosal healing ? Proctitis Left-sided colitis Pancolitis • • • Diarrhoea Tenesmus, urgency Bloody diarrhoea • Weight loss • • Faecal incontinence Sometimes proximal • Fever • constipation Passage of mucus and fresh • Clinically significant blood loss blood • Abdominal pain

Colon capsule: next tool for assessing mucosal healing in IBD ? Erosions, oedema, erythema Erosions Performances of colon capsule in detecting inflammation with endoscopy as gold standard Diagnosis of active UC lesions 68 True positive, n 5 False positive, n 15 True negative, n Pseudo polyps Mosaic pattern 8 False negative, n 96 Total, N 89 (80 – 95) Sensitivity, % (95% CI) 75 (51 – 90) Specificity, % (95% CI) 93 (84 – 97) Positive predictive value, % (96% CI) 65 (43 – 83) Negative predictive value, % (96% CI) CI = confidence interval Ksung J, et al Endoscopy 2011