1. HOT TOPIC IN GASTROENTEROLOGIA 2013
TEN TOPIC IN TEN MINUTES
IBD: cosa è cambiato nella terapia.
Sara Onali, MD, PhD
U.O.C. di Gastroenterologia
Dipartimento di Medicina dei Sistemi
Università di Roma Tor Vergata

2. INFLAMMATORY BOWEL DISEASE
CROHN’S DISEASE
• Can involve all gut
• Transmural inflammation
• Focal lesions
• Post-operative recurrence
ULCERATIVE COLITIS
10%
Undefinited
colitis
• Involve rectum-colon
• Mucosal inflammation
• Continuous lesions
• No recurrence

3. EPIDEMIOLOGY
• Increase incidence 1980-90
• Bimodal incidence 15-40/60
• No difference between sex
• Increase incidence among Askenatzi

4. The European Crohn’s & Colitis Organization’s Epidemiological Committee study
(ECCO-EpiCom) recently investigated the occurrence of IBD in Europe (2010).
Prevalence of IBD 2.5– 3 million people in Europe and 1–1.5 million in North America
Incidence rates 0.1–20.2 for CD and 0.5–31.5 per 100 000 p-yrs in UC
Munkholm et al Curr Opin Gastroenterol 2013

5. Pathophysiology of IBD:
Complex and multifactorial disease
Intestinal inflammation
due to an
unappropriated
response to gut
microbiota in genetically
predisposed subject

6. Remission
Inflammatory flare
Natural history of IBD
Pariente B Inflamm Bowel Dis 2012

7. Clinical approach to the management of IBD
Disease
subtype
Goals
Patient’s
needs

8. Clinical approach to the management of IBD
PREREQUISITES FOR MEDICAL TREATMENT
Site(s)
Disease
subtypes
Extent
localized – segmental
extensive
Behaviour
Drugs
Disease activity
Patients’
needs
Goals Options

9. ULCERATIVE COLITIS: CLINICAL PATTERNS BY SITE/EXTENT
Endoscopic Montreal classification
a. Ulcerative proctitis (limited to the rectum)
b. Left-sided colitis (up to the splenic flexure)
c. Extensive colitis
EXTENSIVE
COLITIS
LEFT-SIDED
COLITIS
DISTAL
COLITIS
Satsangi et al, Gut 2006.
Gasche C, Inflamm Bowel Dis 2000.

10. CROHN’S DISEASE SUBGROUPING: Crohn’s colitis
Non StricturingNon penetrating
Stricturing
Penetrating

11. CROHN’S DISEASE SUBGROUPING: Crohn’s ileitis
Non Penetrating-non stricturing
Stricturing
Penetrating

12. Clinical approach to the management of IBD
The many goals of medical treatment
Inducing
remission
Goals
Maintaining
remission
Meeting specific
Goals
Preventing/treating
complications
Mucosal healing/deep remission

13. Clinical approach to the management of IBD
Defining variables
Crohn’s Disease
Remission:
Patients with a CDAI <150.
Response:
A ΔCDAI of ≥−100 points.
Ulcerative colitis
Remission:
Complete resolution of symptoms
and endoscopic mucosal
healing....in clinical practice meant
a stool frequency ≤3/day with no
bleeding and no urgency.
Responce:
Decrease in the activity
index of 30%, plus a decrease in
the rectal bleeding and
endoscopy subscores
Sandborn Gastroenterology 2002
D’Haens Gastroenterology 2007

14. Clinical approach to the management of IBD:
A Treatment Pyramid based on Severity
Drugs
Severe
Anti-TNF
strategies
Surgery
6MP/AZA
/MTX
Moderate
Systemic Corticosteroids
Mild
Non-systemic Steroids
Antibiotics/Probiotics
Aminosalicylates

16. Inducing remission in CD
Adapted from Travis SPL et al Gut 2006
Indication
Drug
EL
Rec. grade
Mild active IC
Mild active C
Budesonide
Salazopyrin
2a
1b
B
A
Moderate active IC
Budesonide
AZA/6MP
Syst. steroids
1a
1a
A
A
Moderate relapsing
Steroids + in
Anti Tnf-s
AZA/6MP pts
selected
1a
B
Severe IC
Steroids +/Anti Tnf-s
AZA/6MP
Anti TNFs+/-ISS
1a
A
B
1b
B
Severe relapsing Steroid
refractory/ dependent
Distal colitis
Topical 5ASA
5
D
Poor prognosis pts early introduction of ISS, MTX and or anti-TNF therapy [EL5 RG D].
All currently available anti-TNF appear to have generally similar efficacy and adverse-event profiles for
inflammatory (‘luminal’) Crohn's disease, the choice depends on availability, route of delivery, patient
preference, cost and national guidelines [EL5, RG D].
Dignass et al JCC 2010

17. Rate of remission of anti-TNFά therapy for CD
INFLIXIMAB
ACCENT I (remission rates at 4 wks)
(Response rates 4 wks)
Infliximab vs PL 33% vs 4% P=0.01 Infliximab vs PL 65% vs 417% P=0.01
Hanauer SB Lancet 2002.
ACCENT II (remission rates at 54 wks) (Response rates at 54 wks)
Infliximb vs PL 23% vs 19% P<0.01
Infliximb vs PL 46% vs 23% P<0.01
Sands BE, Clin Gastroenterl Hepatol 2004.
CERTOLIZUMAB
PRECISE I
Certolizumab Pegol vs PL 35% vs 27% P=0.02 at Wks 6
Certolizumab Pegol vs PL 23% vs 16% P=0.02 at wks 26
PRECISE I
Certolizumab Pegol vs PL 48% vs 29% P<0.001 at Wks 26
Sandborn WJ, N Engl J Med 2007.
Schreiber S N Engl J Med 2007.

18. Rate of remission of anti-TNFά therapy for CD
ADALIMUMAB
CLASSIC I (remission rates at 4 wks)
40mg/20mg vs PL 18% vs 12% P=0.36
80mg/40mg vs PL 24% vs 12% P=0.6
120mg/80mg vs PL 36% vs12% P=0.01
CLASSIC I (response rates at 4 wks)
40mg/20mg vs PL 54% vs 37% P<0.05
80mg/40mg vs PL 59% vs 37% P=0.01
120mg/80mg vs PL 59% vs 37% P=0.01
Hanauer SB et al.Gastroenterology 2006.
CLASSIC II (remission rates at 56 wks)
40mg eow vs PL 79% vs 44% P<0.05
40mg ew vs PL 83% vs 44% P<0.05
CLASSIC II (response rates at 56 wks)
40mg ew vs PL 89% vs 72% P<0.05
Sandborn WJ et al Gut 2007.
CHARM (remission rates in maintenance)
26 wks
56wks
40mg eow vs PL 40% vs 17% P<0.01
40mg eow vs PL 40% vs 17%
P<0.01
40mg ew vs PL 47% vs 17% P<0.01
40mg ew vs PL 47% vs 17% P<0.01
Colombel JF et al. Gastroenterology 2007.

19. Inducing remission in UC
Site
Proctitis
Indication
Mildmoderate
Refractory
Left-side
Mildmoderate
Drug
EL
Rec.grade
5 ASA topic/os 1b
A
ISS/Biol
C
4
B
Steroids
Nn resp ASA
5 ASA topic/os 1b
1b
C
1b
B
Steroids
Severe
Extensive
Mildmoderate
ACT 1
Clinical Remission at Week 8 and Week 30
*p<0.001
†p=0.002
‡p=0.001
5 ASA topic+os 1a
Steroids
Non responder
1b
ISS/anti TNF
A
C
38.8*
32.0
†
Week 8
Placebo
1b
33.9
‡
36.9*
15,7
14,9
Anti Tnfs/CYS
)
%
(
s
e
a
f
n
i
t
p
o
r
P
Severe
Steroid dependence/refractory
100
90
80
70
60
50
40
30
20
10
0
Week 30
5 mg/kg Infliximab
B
10 mg/kg Infliximab
Dignass et al JCC 2012

20. Maintaining
remission

21. MAINTAINING REMISSION IN CROHN’S DISEASE
Mantenance with oral 5-ASA is a treatment option (EL5, RG D), but there is no
Mantenance with oral 5-ASA is a treatment option (EL5, RG D), but there is no
evidence for its efficacy[EL1b, RG B]. The odds ratio for 6 studies where
evidence for its efficacy[EL1b, RG B]. The odds ratio for 6 studies where
participants were followed up for 12 months was 1.00 (95%CI 0.80-1.24).
participants were followed up for 12 months was 1.00 (95%CI 0.80-1.24).
C Prantera, F Pallone et al, Gastroenterology 1992, 103, 363-368
Akobeng AK, Cochrane Database Syst Rev 2005
Akobeng AK, Cochrane Database Syst Rev 2005
If remission has been achieved with CS, thiopurine [EL1a, RG A] or methotrexate [EL1b, RG
A] should be considered.
If remission has been achieved with an anti-TNF agent, maintenance with regular anti-TNF
therapy should beconsidered [EL1b, RG B].
Azathioprine may be considered in combination with anti-TNF therapy or is an option as
monotherapy if naïve to thiopurines [EL2b, RG C].
Dignass et al JCC 2010

22. Maintenance remission in UC
The goal of maintenance therapy in UC is to maintain steroid-free
remission, clinically [EL1, RG A] and endoscopically defined [EL2, RG B]
Major determinants
• Disease extent [EL1b, RG B]
• Disease course (frequency of flares) [EL5, RG D]
• Failure of previous maintenance treatment [EL5, RG D]
• Severity of the most recent flare [EL5, RG D]
• Treatment used for inducing remission during the most recent flare [EL5, RG D]
• Safety of maintenance treatment [EL1b, RG B]
• Cancer prevention [EL2a, RG B]
Dignass et al JCC 2012

23. Maintenace remission in UC
Oral 5-ASA are the first line maintenance treatment in pts responding to 5-ASA or steroids
(oral or topical) [EL1a, RG A]
Maintenance with topical 5-ASA is an alternative in proctitis/left-sided colitis [EL1b, RG A]
AZA/6MP is recommended in mild-moderate disease with early or frequent relapse or
intolerant to 5-ASA [EL5, RG D], in steroid-dependent [EL1a, RG A ].
Pts with severe colitis responding to intravenous steroids, intravenous ciclosporin or
infliximab, AZA/6MP should be considered to maintain remission [EL2b, RG3]
In pts responding to anti-TNF agents, both maintaining remission withAZA/6MP [EL4, RGC]
and continuing anti-TNF therapy with or without thiopurines [EL1a, RGA].
Pts responding to infliximab continuing infliximab is also appropriate [EL4, RGC]

24. Mucosal healing/
Mucosal healing/
deep remission
deep remission

25. Mucosal healing and deep remissione as new goal??
There is no validated definition of MH in IBD
The „ideal“ definition of Mucosal Healing (MH) could be complete endoscopic healing
of all inflammatory and ulcerative lesions of the gut mucosa in CD and UC
In CD, an endoscopic response to treatment can be defined as “absence of ulcers” or a
significant change of endoscopic disease activity score (CDEIS or SES-CD).
In UC, an endoscopic response to treatment can be defined as a significant change of
endoscopic disease activity score (Baron score or Mayo endoscopic subscore).
Crohn’s disease
Pineton de Chambrun G, et al. Nat Rev Gastroenterol Hepatol 2010.
Ulcerative colitis

26. • Symptom Improvement
with Mucosal Healing
D’Haens et al. Gastroenterology 1999
• Mucosal Healing in CD at Year 2 Predicts Sustained Clinical Remission
49 pts from SUTD trial
underwent
colonoscopy at yrs 2
and were followed-up
through year 3 and 4
Baert F, et al. Gastroenterology 2010

27. Treatment goal
Goal
Clinical Parameters
Outcomes
Response
Improved symptoms
Improved QoL
No symptoms
Remission
Normal labs
Deep remission
Normal endoscopy
Histological remission
SUSTAINED REMISSION
Decreased
hospitalisation
No surgery
Minimal/no disability

28. Clinical approach to the management of IBD
1. Immunosuppressors (AZA-6MP) are effective in the long term.
2. No evidence for a role of 5-ASA in the maintenance of remission in CD.
3. Infliximab and other anti-TNF drugs are rapidly effective in most cases
and the use of biologics is expanding.
4. Mucosal healing may be achieved. More important in UC.

30. State of art for biological therapy for CD
Target
Compound
Stage of development
TNF-ά
Infliximab
Gov. Approval
TNF-ά
Adalimumab
Gov. Approval
TNF-ά
Certolizumab Pegol
US Gov. Approval
TNF-ά
Golimumab
Phase III
ά4integrin
Natalizumab
US Gov.approval
ά 4β7-integrin
Vedolizumab
Phase III
IL 12/23
ABT-874
Phase II
IL 12/23
Ustekinumab
Phase II
IL-6 receptor
Tocilizumab
Phase II
CD3
N1-0401-01
Phase I/IIa
CD40
Ch5D12
Phase I
CTLA-4
Abatacept
Phase III
CD20
Rituximab
Phase III
IL-17
AIN457
Phase II

31. However… Management Must Be Tailored to the Individual Patient
Disease activity
43%
0
19%
IBSEN: disease course in
Crohn’s disease over 10 years
32%
3%
Years
10
0
Years
Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8
10
Missing data, 3%
We must intervene with anti-TNF early in:
• Extensive small bowel disease
• Younger patients
• Severe upper GI disease
• Patients with perianal lesions
• Severe rectal disease
• Patients with early stricturing / penetrating disease
• Patients with deep colonic ulcers
Beaugerie L, et al. Gastroenterol 2006;130:650–6

32. A patients’ needs oriented approach to the management
An alternative explanation for symptoms other than active disease should always
Options
be considered (Infection, bacterial overgrowth, bile salt malabsorption,
gallstones may also cause symptoms in patients with known Crohn’s colitis).
Prevalence of Functional Gastrointestinal Disorders (FGD) in IBD
IBD (n=361)
N % (95% CI)
CD (n=239)
N % (95% CI)
UC (n=122)
N % (95% CI)
No FGD
38 10.5 ( 7.4-13.7)
23 9.7 ( 5.9-13.3)
15 12.3 ( 6.4-18.1)
>1 FGD
323 89.5 (86.3-92.6)
216 90.4 (86.6-94.1)
107 87.7 (81.9-93.5)
124 94.7 (90.8-98.5)
74 94.9 (89.9-99.8)
All patients
Patients with active disease
>1 FGD
198 94.7 (91.6-97.8)
Patients with inactive disease
>1 FGD
122 81.9 (75.7-88.0)
*Inactive CD vs. Inactive UC, p=0.17
89 84.8 (77.9-91.6)*
33 75.0 (62.2-87.8)*
Irvine EJ et al 2005