HOT TOPIC IN GASTROENTEROLOGIA 2013TEN TOPIC IN TEN MINUTES

IBD: cosa è cambiato nella terapia.

Sara Onali, MD, PhD

U.O.C. di GastroenterologiaDipartimento di Medicina dei Sistemi

Università di Roma Tor Vergata

CROHN’S DISEASECROHN’S DISEASE ULCERATIVE COLITISULCERATIVE COLITIS

INFLAMMATORY BOWEL DISEASE

• Can involve all gut • Transmural inflammation• Focal lesions• Post-operative recurrence

• Involve rectum-colon • Mucosal inflammation• Continuous lesions• No recurrence

10% Undefinited

colitis

EPIDEMIOLOGYEPIDEMIOLOGY

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

Munkholm et al Curr Opin Gastroenterol 2013

Incidence rates 0.1–20.2 for CD and 0.5–31.5 per 100 000 p-yrs in UC

Prevalence of IBD 2.5– 3 million people in Europe and 1–1.5 million in North America

The European Crohn’s & Colitis Organization’s Epidemiological Committee study (ECCO-EpiCom) recently investigated the occurrence of IBD in Europe (2010).

Pathophysiology of IBD: Complex and multifactorial disease

Intestinal inflammation due to an

unappropriated response to gut

microbiota in genetically predisposed subject

Pariente B Inflamm Bowel Dis 2012

Natural history of IBD

Infla

mm

ator

y fla

re

Rem

issi

on

Diseasesubtype Goals

Patient’sneeds

Clinical approach to the management of IBD

Diseasesubtypes

Goals

Drugs

OptionsPatients’

needs

Clinical approach to the management of IBD

Site(s)

Extentlocalized – segmentalextensive

Behaviour

Disease activity

PREREQUISITES FOR MEDICAL TREATMENT

ULCERATIVE COLITIS: CLINICAL PATTERNS BY SITE/EXTENT

EXTENSIVECOLITIS

LEFT-SIDEDCOLITIS

DISTALCOLITIS

Satsangi et al, Gut 2006.Gasche C, Inflamm Bowel Dis 2000.

Endoscopic Montreal classification

a. Ulcerative proctitis (limited to the rectum)

b. Left-sided colitis (up to the splenic flexure)

c. Extensive colitis

Non Stricturing-Non penetrating

CROHN’S DISEASE SUBGROUPING: Crohn’s colitis

Penetrating

Stricturing

CROHN’S DISEASE SUBGROUPING: Crohn’s ileitis

Stricturing

Non Penetrating-non stricturing

Penetrating

Clinical approach to the management of IBD

The many goals of medical treatment

Maintainingremission

Mucosal healing/deep remission

Inducing remission

Preventing/treatingcomplications

Meeting specificGoals

Goals

Clinical approach to the management of IBD

Defining variables

Crohn’s Disease

Remission:Remission:Patients with a CDAI <150.

Response:Response:A ΔCDAI of ≥−100 points.

Ulcerative colitis

Sandborn Gastroenterology 2002

Remission: 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:Responce:Decrease in the activityindex of 30%, plus a decrease in the rectal bleeding andendoscopy subscores

D’Haens Gastroenterology 2007

Clinical approach to the management of IBD:DrugsA Treatment Pyramid based on Severity

Severe

Moderate

Mild

Systemic Corticosteroids

Aminosalicylates

Surgery

Antibiotics/ProbioticsNon-systemic Steroids

Anti-TNFstrategies

6MP/AZA/MTX

Indication Drug EL Rec. grade

Mild active IC Mild active C

BudesonideSalazopyrin

2a 1b

BA

Moderate active IC BudesonideSyst. steroids

1a1a

AA

Moderate relapsing Steroids + AZA/6MP

1a B

Severe IC Steroids 1a A

Severe relapsing Steroid refractory/ dependent

Anti TNFs+/-ISS 1b B

Distal colitis Topical 5ASA 5 D

Adapted from Travis SPL et al Gut 2006

Inducing remission in CD

AZA/6MP

Anti Tnf-s in selected pts

Anti Tnf-s +/- AZA/6MP

B

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

Poor prognosis pts early introduction of ISS, MTX and or anti-TNF therapy [EL5 RG D].

Rate of remission of anti-TNFά therapy for CD

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

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

PRECISE ICertolizumab Pegol vs PL 35% vs 27% P=0.02 at Wks 6Certolizumab Pegol vs PL 23% vs 16% P=0.02 at wks 26

CERTOLIZUMAB

PRECISE ICertolizumab Pegol vs PL 48% vs 29% P<0.001 at Wks 26

Schreiber S N Engl J Med 2007.

INFLIXIMAB

Hanauer SB Lancet 2002.

Sands BE, Clin Gastroenterl Hepatol 2004.

Sandborn WJ, N Engl J Med 2007.

Rate of remission of anti-TNFά therapy for CD

CLASSIC I (remission rates at 4 wks)40mg/20mg vs PL 18% vs 12% P=0.3680mg/40mg vs PL 24% vs 12% P=0.6 120mg/80mg vs PL 36% vs12% P=0.01

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

CHARM (remission rates in maintenance)26 wks 56wks40mg 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

ADALIMUMAB

Colombel JF et al. Gastroenterology 2007.

Hanauer SB et al.Gastroenterology 2006.

Sandborn WJ et al Gut 2007.

CLASSIC I (response rates at 4 wks)40mg/20mg vs PL 54% vs 37% P<0.0580mg/40mg vs PL 59% vs 37% P=0.01120mg/80mg vs PL 59% vs 37% P=0.01

CLASSIC II (response rates at 56 wks) 40mg ew vs PL 89% vs 72% P<0.05

Site Indication Drug EL Rec.gradeProctitis Mild-

moderate

Refractory

5 ASA topic/os

ISS/Biol

1b

4

A

C

Left-side Mild-moderate

Nn resp ASA

Severe

5 ASA topic/os

Steroids

Steroids

1b

1b

1b

B

C

B

Extensive Mild-moderate

Non responder

Severe

5 ASA topic+os

Steroids

Anti Tnfs/CYS

1a

1b

A

C

Steroid dependence/refractory ISS/anti TNF 1b B

Inducing remission in UC

Dignass et al JCC 2012

Clinical Remission at Week 8 and Week 30ACT 1

14,9 15,7

38.8*33.932.0

36.9*

0102030405060708090

100

Week 8 Week 30

Pro

po

rtio

n o

f P

atie

nts

(%

)

Placebo 5 mg/kg Infliximab 10 mg/kg Infliximab

*p<0.001†p=0.002‡p=0.001

† ‡

Maintainingremission

MAINTAINING REMISSION IN CROHN’S DISEASE

C Prantera, F Pallone et al, Gastroenterology 1992, 103, 363-368

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 participants were followed up for 12 months was 1.00 (95%CI 0.80-1.24).

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 asmonotherapy if naïve to thiopurines [EL2b, RG C].

Dignass et al JCC 2010

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 participants were followed up for 12 months was 1.00 (95%CI 0.80-1.24).

Akobeng AK, Cochrane Database Syst Rev 2005

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]

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]

Dignass et al JCC 2012

Maintenace remission in UC

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]

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]

Mucosal healing/deep remission

Mucosal healing/deep remission

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).

Pineton de Chambrun G, et al. Nat Rev Gastroenterol Hepatol 2010.

Mucosal healing and deep remissione as new goal??

Crohn’s disease Ulcerative colitis

Baert F, et al. Gastroenterology 2010

49 pts from SUTD trial underwent

colonoscopy at yrs 2and were followed-up through year 3 and 4

• Mucosal Healing in CD at Year 2 Predicts Sustained Clinical Remission

D’Haens et al. Gastroenterology 1999

• Symptom Improvement with Mucosal Healing

ResponseResponse

RemissionRemission

Deep remissionDeep remission

GoalGoal Clinical ParametersClinical Parameters

Improved symptomsImproved symptoms

No symptomsNo symptoms

Normal labsNormal labs

Normal endoscopyNormal endoscopy

Histological remissionHistological remission

OutcomesOutcomes

Improved QoLImproved QoL

Decreased Decreased hospitalisationhospitalisation

No surgeryNo surgery

SUSTAINED REMISSIONSUSTAINED REMISSION

Minimal/no disabilityMinimal/no disability

Treatment goal

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.

Clinical approach to the management of IBD

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

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

IBSEN: disease course in Crohn’s disease over 10 years

Dis

ease

acti

vity

0 1010Years 0 Years

43% 19%

3% 32%

Missing data, 3%

However… Management Must Be Tailored to the Individual Patient

Beaugerie L, et al. Gastroenterol 2006;130:650–6

We must intervene with anti-TNF early in:

• Extensive small bowel disease

• Severe upper GI disease

• Severe rectal disease

• Younger patients

• Patients with perianal lesions

• Patients with early stricturing / penetrating disease

• Patients with deep colonic ulcers

An alternative explanation for symptoms other than active disease should always be considered (Infection, bacterial overgrowth, bile salt malabsorption, gallstones may also cause symptoms in patients with known Crohn’s colitis).

IBD (n=361)N % (95% CI)

CD (n=239) N % (95% CI)

UC (n=122) N % (95% CI)

All patients

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)

Patients with active disease

>1 FGD 198 94.7 (91.6-97.8) 124 94.7 (90.8-98.5) 74 94.9 (89.9-99.8)

Patients with inactive disease

>1 FGD 122 81.9 (75.7-88.0) 89 84.8 (77.9-91.6)* 33 75.0 (62.2-87.8)*

*Inactive CD vs. Inactive UC, p=0.17

Prevalence of Functional Gastrointestinal Disorders (FGD) in IBD

Irvine EJ et al 2005

Options

A patients’ needs oriented approach to the management