Dr Alessandro Armuzzi,UOC di Medicina Interna e Gastroenterologia

Complesso Integrato Columbus – Università Cattolica

Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d’interesse in relazione a questa presentazione

e

che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

Alessandro Armuzzi – Daniela Pugliese

U.O.C. di Medicina Interna e Gastroenterologia

Complesso Integrato Columbus – Università Cattolica - Roma

Inflammatory Bowel Disease

IV SessionDiseases of the bowel-liver axis

Increasing incidence of inflammatory bowel disease

Cosnes J, et al. Gastroenterology 2011Vind I, et al. AJG 2006

The global map of IBDCopenhagen City and County

(annual incidence)

> 10/105

5-10/105

< 4/105

Increase inautoimmune diseases

Increase inhost susceptibility

Restricted immunesystem stimulation

Selectivenutrition

Shelteredhousing

Lack ofparasites

Hygiene &sanitation

Clean food& water

New antigenexposure

Modified from Cohen ML. Nature 2000

Decrease ininfectious diseases

Decrease inhost susceptibility

Decrease indisease transmission

Betternutrition

Betterhousing

Antibiotics

Hygiene &sanitation

Safer food& water

Immunizations

The germless theory of immune-mediated disease:

the hygiene hypothesis

“Inflammatory bowel disease, Crohn’s disease and ulcerative colitis, are complex disorders of unknown etiology resulting from an inappropriate inflammatory response to environmental factors

in genetically susceptible individuals”

threshold

IBD

environment

Susceptibilitygenes

subj

ects

0 1 2 3 4 5

2012

IBD susceptibility loci

Lees CW, et al. Gut 2011

Qin J et al, Nature 2010

Bacterial diversity in IBD mucosap<10-6

The intestinal immune systemin health and disease

Abraham C and Cho JH. NEJM 2009

CD activity and progression

Severity of bowel symptoms from diagnosis to 10-year follow-up

43%

3%

19%

32%

Pariente B, et al. IBD 2011Solberg IC, et al. CGH 2007

Cumulative probability of surgery:

10-yr: 38% (95%CI 31–44)

0%

20%

40%

60%

80%

100%

Diagnosis 1-yr 3-yr 5-yr 10-yr 15-yr 20-yr 25-yr

B1 B2 B3

Louis E et al. Gut 2001

p<0.0001

p=0.04

0

20

40

60

80

100

1962-1987 1991-1993

aggressive

moderate

indolent

P=0.002

Copenhagen Co (DK)

• Prospective inception

cohort

• 1962-1987 n. 1160

• 1991-1993 n. 89

Jess T, et al. IBD 2007

UC activity and course patterns

55%

0 10 yrs

0 10 yrs

0 10 yrs

0 10 yrs

37%

6% 1%

IBSEN Study (Norway)

• Prospective inception

cohort 1990-1994

• 519 UC pts

• 10 yrs FU 82%

Solberg IC, et al. SJG 2009

Overall 10-yr colectomy rate: ~10%

Extensive UC 10-yr colectomy rate: ~20%

Current practice in CD

Budesonide/antibiotics/ Aminosalicylates

AZA/6MP/MTXOral systemic steroids

Surgery

IFX/ADA

IV steroids

Inpatient

Outpatient

Anti-TNF alpha

In most clinical scenariostherapy is sequential

Current practice in UC

Aminosalicylates

AZA/6MPOral steroids

Surgery

CsA/IFX

IV steroids

Inpatient

Outpatient

Anti-TNF alpha

In most clinical scenariostherapy is sequential

Prevalence of abnormal hepatic biochemistriesin patients with IBD

Mendes FD, et al. AJG 2007

Alive at last follow-up, N (%):Abnormal 123/136 (90.4%) vs normal 326/331 (98.5%) - P<0.0001

IBD:

� association with a variety of extraintestinal manifestations (EIMs):

joint, skin, eyes, liver are considered the «primary EIMs of IBD»

� ~ 25-40% of patients with at least one EIM

� perianal CD with higher risk for developing EIMs

� one EIM confers a higher likelihood of developing other EIMs

� Pathogenesis: genetic predisposition, autoantigen display, aberrant

self-recognition, immunopathogenetic autoantibodies, IC, cytokine

imbalance, bacterial antigens/toxins, environmental factors

EIMs - Epidemiology

Isaac KL. IBD 2007

Association between IBD and Hepatopancreatobiliary Manifestations

Classification

Navaneethan U, et al. IBD 2010

Association between IBD and Hepatopancreatobiliary Manifestations

Prevalence

Navaneethan U, et al. IBD 2010

IBD genetics: common pathways with other diseases

PSCHLA, CARD9, MST1,IL2RA, IL2/IL21

PBCORMDR3, IRF5,TNFRSF14

Adapted from Lees CWM, et al. Gut 2011

Genetics associations in PSC

Naess S, et al. CRGH 2012

Aetiopathogenesis of autoimmune liver disease

Trivedi PJ and Hirschfield GM. APT 2012

Homing of mucosal lymphocytes in the pathogenesis of hepatic disease that is associated with inflammatory bowel disease.

Adams DH, et al. Nat Rev Immunol 2006

Incidence ratesPrevalence rates

0.9-1.3 per 100.000 population8.5-13.6 per 100.000 population

Age at diagnosis and sex 3°-5°decade; 7:3 male predo minance

Frequency :PSC in UCPSC in CDIBD in PSC

2.4% - 7.5%1.0% - 3.4%60% - 80%, UC >>> CD

Association with IBD actvity Independent

Association with autoantibodies pANCA (65-88%); ANA (24-53%); ASMA (13-20%); AECA (35%); ACA (4-66%); TPO (7-16%); RF (15%)

Median survival from diagnosisto death or OLT

12 - 18 yearsNo difference in PSC-related survivalamong patients with or without IBD

Response to colectomy Independent

Primary sclerosing cholangitis

Characteristics of IBD associated with PSC

Trivedi PJ, et al. CRGH 2012

• Extensive colitis (with right-sided predominance of inf lammatory activity)

• Rectal sparing (51-65%)

• Backwash ileitis (51%)

• Mild/quiescent course

• Increased risk of CRC (up to 30% over 20 years)

• Increased risk of pouchitis in patients undergoing to proctocolectomy with IPAA

• Increased risk of peristomal varices in patients undergoing proctocolectomy

with ileostomy

Algorithm for the diagnosis of PSC

Chapman R, et al. Hepatology 2010

JCC 2010

• Diagnostic accuracy: typical histological lesions in only 13%• In 98% does not change the clinical management• Unnecessary in recent prognostic models• Complications 0.9%

Angulo P, Am J Gastroenterol 2003

PSC DIAGNOSIS

Role of liver biopsy

Current role:

Diagnosis of OVERLAP SYNDROME (3-6% of PSC)

Diagnosis of SMALL DUCT PSC (5% of PSC)

OR 4.09 (95% CI 2.89 - 5.76)

Soetikno RM, et al. Gastrointest Endosc 2002

PSC and Colorectal Cancer in Ulcerative colitis

The risk appears to persist even after OLT or proctocolectomy with IPAA

p<0.001

Broomé U, et al. Hepatology 1995

Recommendations (AASLD)• We recommend full colonoscopy with biopsies in patients with a new

diagnosis of PSC and no previous history or symptoms of IBD (1A).

• In patients with IBD and PSC, we recommend surveillance colonoscopy with biopsies at 1-year to 2-year intervals from the time of diagnosis of PSC to exclude colorectal neoplasia (1B).

• We recommend against the use of UDCA as chemoprevention for colorectal cancer in patients with ulcerative colitis and PSC (1B)

• In adult patients with PSC, we recommend against the use of UDCA as medical therapy (1A)

• We recommend that patients with IBD and PSC should be treated according to guidelines for IBD (1B).

Chapman R, et al. Hepatology 2010

Recommendations (ECCO)

JCC 2008 and 2010

Cholangiocarcinoma (CCA)

Boberg, Scand J Gastroenter 2002; Tawalkar 2005

Cholangiocarcinoma and PSC

Estimated annual risk 0.5-1.5%

Lifetime risk 10-15%

Prevalence rates 4-20%

Time to diagnosis 30-50% within 2 years of

indentifying PSC

Risk factors Elevated serum bilirubin

Variceal bleeding

Proctocolectomy

UC with CRC of dysplasia

Duration of IBD

Polimorphisn of NKG2D gene

Algorithm for the diagnosis of CCA

Chapman R, et al. Hepatology 2010

CholelitiasisIncidence in CD patients ranging from 13-34%

Associated risk factors OR (95%CI)•Age > 50 4.36 (1.93-9.85)•Disease duration 4.26 (1.64-11.1)

•Ileocolonic disease at baseline 2.37 (1.09-5.12)•Lifetime surgery 4.00 (1.69-5.12)•Frequency of clinical recurrences 8.07 (1.03-63.3)•Extension of ileal resection 7.03 (2.56-19.3)•Number of hospitalizations 20.7 (4.73-90.5)•Lenght of hospital stay 24.8 (7.14-86.3)•TPN 8.07 (1.03-63.3)

Parente F, et al. Hepatology 2007

Portal Vein Thrombosis

• Portal vein thrombosis is a rare complication in IBD patients in the nonsurgical setting.

• Patients with IBD have increased platelet counts, factor V and VIII levels, and fibrinogen levels, and decreased antithrombin III levels, all of which can increase the risk of thrombosis. Smoking, active bowel inflammation, and sepsis in the perioperative phase are other suggested risk factors.

Miehsler W, et al. Gut 2004

IBD Unit, Complesso Integrato Columbus, UCSC 2010

Dose-independent reactions (“idiosyncratic ”) usually within 2-4 weeks

pancreatitis, fever, epatotoxicity , skin rash, arthralgia, weakness, diarrhoea, abdominal pain, nausea/vomitin g

Dose-dependent reactionsusually in a subsequent stage

myelotoxicity, epatotoxicity , infections, neoplasia?

Up to 20% IBD patients treated with thiopurines had to discontinue drug therapy due to the occurrence of adverse event s

AZA/6-MP toxicity

Thiopurine metabolism

Patients experiencing toxicity from AZA/6MP

Present DH, et al. Ann Int Med 1989 ; O’Brien JJ, et al. Gastroenterology 1991; Pearson DC, et al. Ann Int Med 1995; Bouhnik Y, et al. Lancet 1996;Khan ZH, et al. Digestion 2000; Warman JI, et al. J Clin Gastroenterol 2003; de Jong DJ et al Eur J Gastroenterol Hepatol 2004

Author(Patients)

Present(396)

O’Brien(78)

Pearson(302)

Bouhnik(157)

Khan(111)

Warman(410)

de Jong(50)

Stop drug due to AENausea

Allergic reactions

Pancreatitis

Hepatitis/abn LFTsLeucopenia

Death related to

Infections (significant)

LymphomaDeath due to

Blood dyscrasia

Death due to

n/an/a

2.0

3.3

0.32.0

0

7.4

0.50.3

0.3

0

10.31.3

n/a

1.3

1.31.3

0

3.9

0

0

8.91.3

2.0

1.3

n/a1.7

0.3

0.3

0

0

5.73.2

0

0

1.311.0

0

2.5

0.6

0

18.03.6

1.8

0

012.6

0

2.7

0

0

n/an/a

3.9

1.2

4.211.5

0

7.1

0.70.2

0.5

0.5

22.06.0

0

4.0

04.0

0

6.0

0

0

Main reasons for AZA discontinuation and outcome of 6-MP therapy

Hindorf U et al APT 2009

Some AZA reactions

might be due to the nitro-

imidazole moiety found in

AZA, which is released to

produce 6-MP

45-73% of patients intolerant to AZA were

able to tolerate 6-MP

Nodular regenerative hyperplasia

Vernier-Massouille G, et al. Gut 2007; Seksik P, et al: IBD 2011

10-year NRH cumulative incidence: 1.28 ± 0.45 %

Independent variables:male gender (P < 0.0001, HR] 8.5, 95%CI 1.9–37.9)small bowel resection >50 cm (P < 0.0001, HR 6.6, 95%CI 2.2–20.0)

Changes in liver biochemistry during MTX use for IBD

Fournier MR, et al. AJG 2010

Gisbert JP, et al. APT 2011

Anti-TNFα and hepatitis B virus infection

HBsAg - /anti HBc - ���� vaccination

HBsAg + ���� prophylaxis with nucleoside analogues

HBsAg - /anti HBc + ���� HBV DNA and monitoring

HSTCL and anti-TNFαααα or AZA/6-MP

Kotlyar DS, et al. CGH 2011

Demographics and outcomes of patients with IBD and HSTCL

Thai A, et al. JCC 2010

LFTs monitoring on IBD treatment

Navaneethan U, et al. IBD 2010