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
• utcomes

UC = ulcerative colitis

UC: outcomes at 5-year follow-up according to early response to steroids

20 40 60 80 100 Relapse Hospitalisation Immuno- suppression Colectomy Clinical and endoscopic remission Clinical no endoscopic remission No remission

Ardizzone S, et al. Clin Gastroenterol Hepatol 2011;9:483–9

* * * * # # #

*p<0.05 vs clinical and endoscopic remission

#p<0.05 vs clinical remission (± endoscopic remission)

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

ACT 1 and ACT 2

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

Kaplan-Meier Estimates of Time to Colectomy in Infliximab-Treated Patients

Week 8 endoscopy score (n=466a)

• No. of

colectomies Week 54 colectomy-free probability (%) p valueb (log rank)

0 (n=120) 6 95 0.0004 1 (n=175) 8 95 2 (n=114) 14 87 3 (n=57) 10 80

aPatients randomised to infliximab. Patients who had colectomy or discontinued before week

8 were not included

bp value indicates the difference in distributions of time to colectomy among the 4 endoscopy

score subgroups

UC: Early mucosal healing with infliximab is associated with reduced risk of colectomy

Colombel JF, et al. Gastroenterology 2011;141:1194–201 UC = ulcerative colitis

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
• f endoscopic healing and outcomes

–is not yet established –may be influenced by treatments

CD = Crohn’s disease

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)

68% 32% 10% 90% 0% 25% 50% 75% 100% 21/31 10/31 3/31 28/31 SES-CD<5 SES-CD>5

Remission Activity p<0.0001 OR 19.6 (95%CI 4.79-80.2)

CD: Early mucosal healing is associated with long-term remission (Extend)

Sandborn WJ , et al. Gastroenterology 2012;142:1102-1111.

Baert F, et al. Gastroenterology 2010; 138(2):463-8

49 patients from SUTD trial underwent colonoscopy at year 2 and were followed-up through year 3 and 4

Remission off-GCS Remission off-GCS & off- IFX New or active draining fistulae SES-CD = 0 (n=24) 71% 63% 4% SES-CD 1-9 (n=22) 27% 18% 23% 0% 25% 50% 75% 100% Patients in remission years 3-4 (%) p=0.036 OR=6.48 (95%CI 1.8-23.4) p=0.032 OR=7.5 (95%CI 1.9-29.3) p=0.009 OR=0.148 (95%CI 0.016-1.38)

CD: Endoscopic healing in CD at year 2 predicts sustained clinical remission (SUTD)

Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8

CD: mucosal healing at one year is associated with a reduced risk of surgery

Proportion of patients not resected

9 8 7 6 5 4 3 2 1

Time after 1-year visit (years)

Hazard ratio = 0.42, 95% CI 0.20–0.89; p=0.027 Adjusted for age and disease extent at diagnosis

1.0 0.9 0.8 0.7 0.6 0.5

83%

No mucosal healing Mucosal healing

69%

IBSEN study: risk of future surgery in patients with mucosal healing at 1 year (n=146)

CD: patients who achieved deep remission* with adalimumab at Week 12 were less hospitalized through week 52 (Extend)

All-cause hospitalisation through Week 52 CD-related hospitalisation through Week 52

17 5 10 15 20 0/11 9/53 All hospitalisation (%) 9 5 20 0/11 5/53 CD-related hospitalisation (%) Deep remission* (Week 12) Non-deep remission* (Week 12) Deep remission* (Week 12) Non-deep remission* (Week 12) 10 15

* 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)

* Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND

† IBDQ remission defined as IBDQ score ≥170

IBDQ remission† at Week 52 64 26

25 50 75

Deep remission* (Week 12) Non-deep remission* (Week 12) Patients in IBDQ remission† (%)

7/11 14/53 p<0.05

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

Louis E, et al. Gastroenterology 2012;142:63-70.

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 Index ≤4 2/19 =5 10/36 =6 13/24 =7 25/28 # relapse Time since inclusion (months) Proportion Global 40/107

# at risk: 115 102 79 63 51 47 39 27 20 12 9

Global and individual curves according to predictive index

0.0 0.2 0.4 0.6 0.8 1.0 3 6 9 12 15 18 21 24 27 30 33

HsCRP = high-sensitivity C-reactive protein; CDEIS = CD endoscopic index of severity

Landi B, et al. Gastroenterology 1992;102:1647–53

20 40 60 80 100 2 4 6 8 10 12 14 16 18

Maintained clinical remission on follow-up

Endoscopic remission (n=33) NO initial endoscopic remission (n=37)

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

0.0 0.2 0.4 0.6 0.8 1.0 6 12 18

Time after randomisation (months) Azathioprine Placebo

Patients at risk (relapses): 40 38 (1) 34 (2) 23 (3) Azathioprine 43 40 (3) 35 (7) 27 (9) Placebo

Randomised, double-blind, placebo-controlled, multicentre azathioprine withdrawal trial in CD

Presence of endoscopic lesions (CDEIS 0) or ulcerations was not a predictor

• f relapse

Lémann M, et al, Gastroenterology 2005;128:1812–8

Remission rate

D.Rumsfeld

Crohn’s disease

• No mucosal ulceration in any of 5

segments

• Absence of mucosal ulceration
• Disappearance of all ulcerative

lesions

• CDEIS ≤2, ≤3, ≤4, ≤6
• SES-CD ≤5
• Rutgeerts score ≤i1

Need for homogenous definition of endoscopic healing

Ulcerative colitis

• Normal, improved, no change or

worse

• Severity of bleeding without

considering ulcers

• UC-DAI≤1
• Mayo≤1
• UCEIS < ?

What is the definition of mucosal healing ?

What is the prognostic endoscopic threshold in CD?

Need for major abdominal surgeries

14.1 14.0 38.4 10 20 30 40 Complete mucosal healing (n=85) Partial mucosal healing (n=43) No mucosal healing (n=86)

n=6 n=12 n=12

Schnitzler F, et al. Inflamm Bowel Dis 2009;15:1295–301

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 Roc Curve for detecting corticoid-free remission at wk 50 using the CDEIS % reduction from baseline to wk 26 Roc Curve for detecting corticoid-free remission at wk 50 using the SES-CD % reduction from baseline to wk 26

Endoscopic response at wk 26 predicts corticoid-free remission at wk 50 (SONIC)

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

After therapy

Mucosal healing and the small bowel ?

Calabrese C, et al. Aliment Pharmacol Ther 2008;27:759–64

UC: is rectosigmoidoscopy enough to assess mucosal healing ?

• Tenesmus, urgency
• Faecal incontinence
• Passage of mucus and fresh

blood

Left-sided colitis

• Bloody diarrhoea
• Sometimes proximal

constipation

• Diarrhoea
• Weight loss
• Fever
• Clinically significant blood loss
• Abdominal pain

Pancolitis Proctitis

Colon capsule: next tool for assessing mucosal healing in IBD ?

Ksung J, et al Endoscopy 2011

Performances of colon capsule in detecting inflammation with endoscopy as gold standard

Erosions, oedema, erythema Erosions Pseudo polyps Mosaic pattern

Diagnosis of active UC lesions True positive, n 68 False positive, n 5 True negative, n 15 False negative, n 8 Total, N 96 Sensitivity, % (95% CI) 89 (80–95) Specificity, % (95% CI) 75 (51–90) Positive predictive value, % (96% CI) 93 (84–97) Negative predictive value, % (96% CI) 65 (43–83)

CI = confidence interval

Confocal endomicroscopy in IBD: the next frontier ?

Normal mucosa Active CD CDEIS<4 with endomicroscopic activity mucosa Mucosal healing at endomicroscopy

Travis S, et al. Gut 2012; 61:535–42 IBD = inflammatory bowel disease

Kaplan-Meier plot of relapse of IBD patients

• ver 12 months after confocal laser

endomicroscopy stratified according to their Watson grade

Confocal endomicroscopy in IBD

Kiesslich R et al. Gut 2012;61:1146–53

Cell shedding Local barrier dysfunction

• I. Normal

Cell shedding confined to single cells per shedding site (eg, figure 1C or D) None

• II. Functional

defect Cell shedding confined to single cells per shedding site Fluorescein signal visible in the intestinal lumen with an intensity the same or brighter than the epithelium or fluorescein plumes out

• f the epithelium into

the lumen (eg, figure 2D)

• III. Structural

defect Microerosions in any

• field. Microerosion is

defined when the lamina propria is exposed to the lumen with multiple cells being shed per site (eg, figure 2E) Fluorescein signal visible in the intestinal lumen with an intensity the same or brighter than the epithelium or fluorescein plumes out

• f the epithelium into

the lumen (eg, figure 2E)

Table 1 Endomicroscopic grade (Watson grade) for in vivo identification of local barrier dysfunction

Watson I Watson II/III Remission Time (month) 2 4 6 8 10 12 14 1.0 0.8 0.6 0.4 0.2 0.0 p<0.001

Is mucosal healing the good target ? (The treat-to-target approach)

Symptoms Damage by treating beyond symptoms Symptoms Inflammation molecular Inflammation transmural Inflammation histological Damage Inflammation mucosal

UC: discordance between endoscopy and clinical symptoms

Clinical Response, Remission, and Mucosal Healing at 6 Weeks (vedolizumab) 25.5 5.4 24.8 47.1 16.9 40.9

5 10 15 20 25 30 35 40 45 50

Clinical Response Clinical Remission Mucosal Healing Placebo VDZ

P<0.01 P<0.01 P<0.01 Δ 21.7 11.6, 31.7 Δ 11.5 4.7, 18.3 Δ 16.1 6.4, 25.9 95% CI: Patients, %

Induction ITT Population

Feagan B et al. DDW 2012

UC: discordance between endoscopic and histological healing (n=103)

Individual Geboes histological scores plotted against Mayo endoscopic scores

Rosenberg L, et al. Clin Gastroenterol Hepatol 2013;11:991-996.

Predictors of relapse in UC

Hazard ratio (95% CI) p value Age 0.4a (0.2–0.7) 0.003 Basal plasmacytosis 4.5 (1.7–11.9) 0.003

• No. of prior

relapses Women Men 1.6b (1.2–1.9) 0.93 (0.7–1.3) <0.001 0.64

Bitton A, et al. Gastroenterology 2001;120:13–20

0.25 0.50 0.75 1.00 0.00 Absence

Proportion of patients in remission

2 4 6 8 10 12 Presence Basal plasmacytosis

Time on study (months)

aPer decade bNo significant differences in WBC, Hb, and albumin

CI = confidence interval WBC = white blood cell count; Hb = haemoglobin

UC: histological remission predicts lower hospitalisation rates

Burger D, et al. J Crohn’s Colitis 2011;5:S4 Clinical remission Endoscopic remission Histological remission Hazard ratio (95% CI) 0.24 (0.05–1.10) 0.53 (0.18–1.56) 0.27 (0.07–0.95) p value 0.07 0.25 0.048

Hospitalisation

10 20 30 40

Time (months)

Endoscopic

0.0 0.5 1.0

Endoscopic remission No endoscopic remission

10 20 30 40

Time (months)

Clinical

0.0 0.5 1.0

Clinical remission No clinical remission

10 20 30 40

Time (months)

Histological

0.0 0.5 1.0

Histological remission No histological remission

Histological remission is associated with a 4-fold reduction in hospitalisation

Variable

• No. patients (%)

Odds ratio (95% CI) p value Controls (n=136) Cases (n=68) Colonoscopy inflammation score* 1.89 (0.52) 2.22 (0.78) 2.54 (1.45–4.44) 0.001 Histological inflammation score* 2.05 (0.41) 2.38 (0.56) 5.13 (2.36–11.14) <0.001 Family history of colorectal cancer 18 (14) 7 (12) 1.09 (0.40–2.94) 0.17 Primary sclerosing cholangitis 2 (2) 4 (6) 4.00 (0.73–21.84) 0.11 Mesalamine use 122 (90) 65 (96) 2.38 (0.67–8.54) 0.32 Azathioprine use 37 (28) 12 (18) 0.73 (0.30–1.78) 0.22 Folate supplement 5 (4) 1 (1) 0.40 (0.05–3.42) 0.40 Current smoker 9 (7) 2 (4) 0.43 (0.08–2.23) 0.37

Severity of inflammation is a risk factor for colorectal neoplasia in UC

Rutter M, et al. Gastroenterology 2004;126:451–9 *Segmental colonoscopic and histological inflammation was recorded by using a simple score (0, normal; 1, quiescent/chronic inflammation; and 2, 3, and 4, mild, moderate, and severe active inflammation, respectively).

In multivariate analysis, the histologic score was the only risk factor (OR, 4.7; 95% CI, 2.1 – 10.5)

CD: Should we look beyond the mucosa ?

Mucosal healing is a too limited target !

D.Rumsfeld

What needs to be done TODAY

• Validation of significant thresholds for mucosal

healing in the colon and the small bowel

• Prospective studies
• Long-term studies with significant endpoints
• Comparing different therapeutic approaches

using mucosal healing as a therapeutic goal as compared with clinical symptoms

• In early patients

Current trials that can help answer these questions

CALM

 Active moderate/severe CD  Endpoint: mucosal healing

at Week 56

 Tight control of disease

activity using stringent criteria (CDAI, steroid use, hs-CRP, faecal calprotectin) vs management using less stringent criteria (CDAI, steroid use)

REACT 2

 Active luminal CD (HBI >4)  Endpoint: CD-related

complications at 1 year (hospitalisation for CD- related surgery, or bowel damage not requiring hospitalisation)

 Enhanced care algorithm

vs step care algorithm