Colangiopatie autoimmuni ed epatiti

autoimmuni, malattie prevalenti nella donna

Annarosa FloreaniDept. of Surgery, Oncology and Gastroenterology,

University of Padova

16 settembre 2017

Annarosa Floreani, MD, Dept. of Surgery, Oncology and Gastroenterology, University of Padova, Italy

Declares to have participated over the last 12 months in the Advisory Committee of the PBC Group

sponsored by Intercept

Condizioni autoimmuni del fegato

AIH necro-infiammazione

PBC colestasi

PSC colestasi

overlap syndromes necro-infiammazione

+ colestasi AIH/PSC

AIH/PBC

predisposizione genetica

fattori triggers (agenti infettivi, farmaci, tossici)

difetti dell’immunoregolazione

Eziopatogenesi

B

Co- stimuli

Class I

Class II

K

TSTS

APC

P

TNF-aIFN-g

M

TCTC

TH2TH2

TH0

cellLiver

IL-1IL-1

B

Co- stimuliCo- stimuli

Class I

Class II

IL-2IL-2

IL-12IL-12

K

TsTs

IL-4IL-4IL-10IL-10

APC

P

TNF-aTNF-aIFN-gIFN-g

MIFN-gIFN-g

TcTc

Th2Th2

cellLiver

IL-4IL-4

Th0

Th1

B

Co- stimuli

Class I

Class II

K

TSTS

APC

P

TNF-aIFN-g

M

TCTC

TH2TH2

TH0

cellLiver

IL-1IL-1

B

Co- stimuliCo- stimuli

Class I

Class II

IL-2IL-2

IL-12IL-12

NK

TsTr

IL-4IL-4IL-10IL-10

APC

P

TNF-aTNF-aIFN-gIFN-g

M

IFN-gIFN-g

TcTc

Th2Th2

cellLiver

IL-4IL-4

Th0

Th1

Autoimmune Hepatitis

Interface

hepatitis

D. Vergani et al, Semin Immunopathol 2009

AIH Profilo autoanticorpale

Caratteristica

Tipo I ANA, SMA Bimodale

Tipo II LKM

(P-450 IID6)

Pediatrica (2-14)

Rara in adulti

(associazione con HCV)

Tipo III SLA Adulti (rara)

De novo AIH

(post OLTX)

ANA, SMA, LKM,

Classificazione

Anti-smooth muscle (SMA) &

Anti-nuclear (ANA)

autoantibodies

Epatite autoimmune Tipo 1

Liver Kidney Microsomal antibody

Epatite autoimmune tipo 2

DIAGNOSIS OF AIH – Recommendations

• AIH should be considered in any patient with acute or chronic liver disease,

particularly in the context of hypergammaglobulinemia (II-2)

• Prompt and timely diagnosis is crucial as untreated AIH has a high mortality

rate (I)

• Approximately 1/3 of adult patients and about ½ of children with AIH have

cirrhosis at presentation (II-2)

• Acute presentation of AIH can occur and may manifest as acute exacerbation

form of previously undiagnosed AIH or new onset acute AIH without

histological changes suggestive of chronic disease (II-2)

• AIH is associated with a broad variety of other autoimmune diseases (II-2)

• All children with a diagnosis of AIH should undergo (MR-) cholangiography to

exclude autoimmune sclerosing cholangitis (II-2)

• AIH patients with cirrhosis should undergo liver US in 6-month-intervals for

HCC screening (II-2)

AIH I

FORMA ACUTA

(30%)

FORMA CRONICA

(70%)

ANA/ASMA

età giovane-

adulta

AIH II

anti-LKM 1

età giovanile-

pediatrica

età adulta (donne,

HCV positività)

FORMA ACUTA

(30-40%)

prognosi peggiore

AIH III

anti-SLA/LP

età giovane-

adulta

clinica = AIH I

Presentazione clinica

Simplified criteria for the diagnosis of AIH

Probable AIH: >6 cut-off (88% sensitivity, 97% specificity)

Definite AIH: >7 cut-off (81% sensitivity, 99% specificity)

Hennes EM et al, Hepatology 2008

Diagnostic Algorithm for AIH usingroutine autoantibody testing

Probable or possible AIH vs DILI

0.5-1 mg/Kg predniso(lo)ne

Response

Relapse

Treatment of

AIH

Avoid this

drug

In future

Consider

alternative

diagnosis

Non

response

No

relapse

DILI*Definite AIH

Taper steroids

until withdrawal

Therapeutic options for AIH remission according to the AASLD guidelines

Therapeutic options for AIH remission according to the EASL guidelines

Follow-up of AIH patients who have achieved remission

Remission

Stable remission on monotherapy

for >24 (36) months

Reduce immunosuppression

stepwise

Remission

(normal ALT/normal IgG)

Taper steroids, adapt

azathioprine-dose

(consider checking 6-TG

levels) as required to

retain remission

Relapse

Taper out immunosuppression

completely (consider prior liver

biopsy)

Stable remission without

treatment

Monitor life-long

(3 monthly for 1 year, then 6-

monthly)

Re-induce remission with

predniso(lo)ne (induction

dose

Long-term (life long?)

maintenance treatment

New immunotherapies for AIH

• 11 pts non responders to standard Tx

• Age 28-70; 7F, 4M

• 4 stopped Infliximad for severe infections

Liver Transplantation

End-stage liver disease

– Complications of portal hypertension

– Hepatocellular carcinoma

Fulminant liver disease

– Acute liver injury

– Acute decompensation superimposed on chronic liver injury

Results

– 5 yr pt and graft survival: 80-90%

– Recurrence: 15-40%

– Higher rates of acute and chronic rejection

PBC and PSC

Stima per 100.000

PBC epidemiology: Reported sex ratios in population-based studies

Scientific Report 2016

PBC epidemiology: Gender distribution

Rate of incident PBC cases by age group during 2000-2008 in the Netherlands

Boonstra et al. Liver Int 2014

Lombardia population

Inhabitants (about

10.000.000)

M:F PBC RATIO = 1:2

Denmark population

Inhabitants (about

5.500.000)

M:F PBC RATIO = 1:4

Scientific Report 2016

Global PBC Study Group

Dallas

Edmonton

Seattle

Toronto

Rochester

Birmingham

London

Paris

Barcelona

Leuven

Amsterdam

&

Rotterdam

MilanPadua

W.J. Lammers, MD PhD

> 20 centers world-wide - European and North American medical centers> 20 centers world-wide - European and North American medical centers

Acknowledgments

All members of the Global PBC Study Group

Networking story in PBC

2011 2012

Swiss PBC

Austro-German

PBC

2016-17

ERN-RARE

LIVEREuropean Reference

Network

ERN RARE LIVER

Current Membership•Country Partner

•Belgium Ghent University Hospital

•Belgium University Hospital KU Leuven

•Belgium Université Catholique de Louvain (St Luc)

•Denmark Rigshospitalet University of Copenhagen

•France Hôpital Bicêtre

•France Hôpital Beaujon

•France Hôpital Saint-Antoine

•Germany University Hospital Aachen

•Germany Universitaetsklinikum Tübingen

•Germany Hannover Medical School

•Germany Universitaetsklinikum Hamburg-Eppendorf

•Germany Saarland University Medical Center

• Italy Azienda Sanitaria Socio Assistenziale

(ASST)-Monza, Ospedale San Gerardo

• Italy Azienda Ospedaliera - Universitaria di Padova

• Italy Azienda Sanitaria Socio Assistenziale (ASST)-Santi

Paolo e Carlo

•Netherlands University Medical Center Groningen

•Netherlands Radboud UMC

•Netherlands Academic Medical Centre, University of Amsterdam

•Poland Medical University of Warsaw Hospital

•Portugal Centro Hospitalar Universitario de Coimbra

•Spain Hospital Universitario La Paz

•Spain Hospital Clínic de Barcelona

•Sweden Karolinska University Hospital

•Sweden Sahlgrenska University Hospital

•UK Birmingham Children's Hospital NHS Foundation Trust

•UK University Hospitals Birmingham NHS Foundation Trust

•UK Royal Free London NHS Foundation Trust

•UK The Newcastle upon Tyne Hospitals NHS Foundation

Trust

PBC/HCV

• 14/170 (8%)

• At presentation, the HCV-infected PBC group had significantly lower levels of ALP, GGT, and IgM than the AMA+ or AMA- PBC patients (p<0.01).

• Increased risk for HCC

• 9/76 (11.8%)

• PBC/HCV+ vs PBC/HCV- 1:3

• HCV+ significantly higher Child-Pugh and MELD

• Higher incidence of HCC

• No difference in survival

Floreani A et al. AJG 2003 Chen W-H et al, Ann Hepatol 2013

A total of 171 PBC patients were considered eligible for the study (160

females, 11 men, mean age 53 years, range 29-83 yrs).

55 of them (32.1%) at presentation fulfilled the criteria for MS.

Metabolic syndrome

Floreani et al, J Clin Gastroenterol 2015

The occurrence of cardiovascular events during the

follow-up was significantly higher in patients with MS

(p< 0.01).

p<0.01%

Cardiovascular events

Floreani et al, DLD 2015

At presentation, 221 patients (61.2%) had at

least one EHA condition

Thyroid diseases in PBC

Floreani A, et al, Am J Gastroenterol 2017

150/921 (16.3%)

5

Primary endpoint: achieving alkaline phosphate (ALP) <1.67x ULN and a ≥15% reduction in ALP and a total bilirubin ≤ULN

POISE: Significant Reductions in ALP Within 2

Weeks

* p-values from an ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor.

Data are least squares mean(SE)

*p<0.0001 vs. placebo

T im e (m o n th s )

% A L P

-4 0

-2 0

0 P la c e b o (n = 7 3 )

T itra tio n O C A (n = 7 0 )

1 0 m g O C A (n = 7 3 )

0 6 1 2

*

*

*

* *

*

*

*

*

*

% Drop in

ALP

Re

sp

on

de

rs

(%

)

0 .5 3 6 9 1 2 O L E

3

O L E

6

O L E

9

O L E

1 2

O L E

1 5

O L E

1 8

0

2 0

4 0

6 0

8 0

P la c e b o U D C A , n

O C A 5 -1 0 m g U D C A , n

O C A 1 0 m g U D C A , n

M o n th s

D o u b le -B lin d P h a s e

R a n d o m iz e d T r e a tm e n t

O p e n -L a b e l E x te n s io n

A ll R e c e iv e O C A

5 m g T it r a t io n

***

***

***

***

***

***

***

***

*** ***

D B T r e a tm e n t G r o u p

7 3 7 37 3 7 3 7 3

5 9 5 96 4 6 0 5 5 5 5

7 0 6 27 07 0 6 07 0 6 37 0 6 2 5 7 5 7

7 3 6 17 37 3 5 97 3 6 47 3 5 9 5 8 5 9

P la c e b o p a t ie n t s s t a r t e d O C A d u r in g t h e o p e n - la b e l e x t e n s io n , n

Significant Increase in OCA-Treated Patients Meeting Primary Endpoint During the Double-Blind Phase

• ***p<0.0001; p-values for comparing treatments in the DB phase are obtained using CMH General Association test stratified by randomization strata factor; OLE study ongoing. During the DB patients with missing values were considered non-responders. During the DB phase, 3 patients discontinued from Placebo, 7 patients from OCA 5-10 mg, and 9 patients from 10 mg OCA.

OCA Treatment Showed Sustained Improvement in ALP Over Time

• ***p<0.0001; †p-value for comparing active treatments to Placebo is obtained using an ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor, p-value based on LS mean difference values; ‡p-value for the within treatment comparisons are obtained using a paired t-test.

3 6 9 1 2

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

M o n th s

Me

an

(S

D)

AL

P (

U/L

)

B L

A L P 1 .6 7 x U L N

O L E

3

O L E  

6

O L E  

12

U L N

5 m g T itra tio n

D o u b le -B lin d P h a s e

R a n d o m iz e d T re a tm e n t

O p e n -L a b e l E x te n s io n

A ll R e c e iv e O C A

O L E

9

O L E

 15

O L E  

18

O C A 5 -1 0 m g U D C AP la c e b o U D C A O C A 1 0 m g U D C A

P la c e b o P a tie n ts R e c e iv in g O C A d u r in g O L E U D C A

3 6 9 1 2

4

6

8

1 0

1 2

1 4

1 6

2 0

2 4

2 8

M o n th s

Me

an

(S

D)

To

tal

Bil

iru

bin

(u

mo

l/L

)

B L O L E

3

O L E  

6

O L E  

9

O L E  

12

D o u b le -B lin d P h a s e

R a n d o m iz e d T re a tm e n t

O p e n -L a b e l E x te n s io n

A ll R e c e iv e O C A

U L N

5 m g T itra tio n

O L E  

15

O L E

18

P la c e b o U D C A O C A 5 -1 0 m g U D C A O C A 1 0 m g U D C A

P la c e b o p a tie n ts re c e iv in g O C A d u r in g O L E U D C A

Total Bilirubin Remained Stable With OCA Treatment

• *p<0.05, **p<0.01, ***p<0.0001; †p-value for comparing active treatments to placebo is obtained using an ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor, p-value based on LS mean difference values; ‡p-value for the within treatment comparisons are obtained using a paired t-test.

Sustained Reduction In Markers of Hepatic Damage: AST and ALT

• Reductions in AST and ALT are statistically significant (p<0.05) for all OCA -treated groups in the DB phase† and all groups in the OLE phase‡

• †p-value for comparing active treatments to placebo is obtained using an ANCOVA model with Baseline value as a covariate and fixed effects for treatment and randomization strata factor, p-value based on LS mean difference values; ‡p-value for the within treatment comparisons are obtained using a paired t-test.

3 6 9 1 2

0

2 0

4 0

6 0

8 0

1 0 0

M o n th s

Me

an

(S

D)

AS

T (

U/L

)

B L O L E

3

O L E  

6

O L E  

9

O L E  

12

5 m g T itra tio n

D o u b le -B lin d P h a s e

R a n d o m iz e d T re a tm e n t

O p e n -L a b e l E x te n s io n

A ll R e c e iv e O C A

O L E  

15

O L E  

18

O C A 5 -1 0 m g U D C AP la c e b o U D C A O C A 1 0 m g U D C A

P la c e b o p a tie n ts re c e iv in g O C A d u r in g O L E U D C A

3 6 9 1 2

0

2 0

4 0

6 0

8 0

1 0 0

M o n th s

Me

an

(S

D)

AL

T (

U/L

)B L O L E

3

O L E  

6

O L E  

9

O L E  

12

5 m g T itra tio n

D o u b le -B lin d P h a s e

R a n d o m iz e d T re a tm e n t

O p e n -L a b e l E x te n s io n

A ll R e c e iv e O C A

O L E  

15

O L E

 18

AST (U/L) ALT (U/L)

OCA Treatment Decreased Total Bilirubin Over Time

• *p<0.05, **p<0.01, ***p<0.0001

3 6 9 1 2

5

1 0

1 5

1 6

1 8

2 0

T im e (M o n th s )

Me

an

(S

D)

To

tal

Bil

iru

bin

(u

mo

l/L

)

B L L T S E

3

L T S E  

6

L T S E  

9

L T S E  

12

D o u b le -B lin d P h a s e

R a n d o m iz e d T re a tm e n t

O p e n -L a b e l P h a s e

A ll R e c e iv e O C A

U L N 5 m g T itra tio n

P la c e b o U D C A T itra t io n O C A U D C A O C A 1 0 m g U D C A

Frequent AEs (≥5%)

At End of Study Pruritus Experience Was Similar for All

Subjects Using a Visual Analog Score

T im e (m o n th )

LS

Me

an

(S

E)

Ch

an

ge

in

Pru

rit

us

VA

S S

co

re

fro

m B

as

eli

ne

-1 0

0

1 0

2 0

3 0

P la c e b o (n = 7 3 ); B L V A S 2 5 .3 3 .3

0 6 1 2

T itra tio n O C A (n = 7 0 ); B L V A S 2 1 .2 3 .1

1 0 m g O C A (n = 7 3 ); B L V A S 2 0 .2 2 .9

*

*

*

*p<0.05 vs placebo, p-values from an ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata

factor.

VAS scores range from 0 (no pruritus) to 100 (severe pruritus)

Titration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if well tolerated & ALP ≥1.67x ULN or bilirubin >ULN

La Determina dell’AIFA n. 1392/2017 è stata pubblicata in Gazzetta Ufficiale (GU Serie Generale n.196 del 23-08-2017)

FIBRATES

MDR3PPARa

O-

oxidation

enzymes

LTB4

ApoAII

ICAM-I

VCAM1

Anti-inflammation

Biliary phospholipid

secretion

Inactivation of hydrophobic

bile acids

Protection of BECs

NF-kB

IL-1, IL-6

COX2

PGE E2

Th2

Ig production

Autoimmunity From Dohmen et al. (modified) WJG 2004

Use of PPAR agonists (fibrates ) in

PBC PBC

Baseline characteristics

AASLD 2016

0 1 0 1 0 1

Overall

p<0.001

Fenofibrate

p<0.001

Bezafibrate

p<0.002

ALP decrease with Feno- and Bezafibrate

Time (years)

AASLD 2016

ALP (xULN)

Normal ALP after 1 year is associated with better free

transplant-free survival

Normal ALP at 1 year

Abnormal ALP at 1

year

47

81

35

6628

47

15

35

11

19

p = 0.03Transplant free survival (%)

AASLD 2016

2-year multicenter, double-blind, randomized, placebo-controlled

trial of bezafibrate (400 mg/d) + UDCA

Corpechot et al EASL 2017

Inadequate

biochemical

response to

UDCA

(Paris-2

criteria)

Randomization

N=100

Premature termination

N=4

Bezafibrate

400 mg/dl

N=50

Placebo

N=46

Placebo

N=44

Bezafibrate

400 mg/dl

N=50

Bezafibrate

400 mg/dl

N=48

Placebo

N=50

Premature termination

N=2

Premature termination

N=2

Recruiting centers: 21

Recruiting period: 22/10/2012 – 22/10/2014

UDCA 13-15 mg/Kg/d

M0 M3 M6 M9 M12 M15 M18 M21 M24

Baseline characteristics

Corpechot et al EASL 2017

M24 complete biochemical responsePrimary endpoint

Corpechot et al EASL 2017

30%

M24 normal alkaline phosphatase levelSecondary endpoint: M24 normal ALP

Corpechot et al EASL 2017

67%

Genetic

predisposition

Association with IBD >70%

Pathogenesis of primary sclerosing cholangitis

Hepatocyte

Bile ducts

Microbiota(bacterial pathogens)

Aberrant homing

of intest.T-cells

PSC and Genetic Associations

• Integration of Genetics and Environment?

Karlsen et al. J Hepatol 2015;62:S6–S14.

Environmental risk factors

• Not well understood!

• Smoking is protects against ulcerative colitis, and

this is also seen in patients who have both PSC

and colitis

• Two independent studies have suggested a

negative association between coffee

consumption and PSC.

Lammert et al Clin Gastroenterol Hepatol 2014; 12:1562-8

Andersen IM et al Clin Gastroenterol Hepatol 2014; 12: 1019-28.

Genome Wide Association Studies in PSC

HLA

IL2RABCL2L11 MST1

Melum E et al, Nat Genet 2011: 43: 17-19

Shared and unique genetic risk

PBC PSC

Genetics of PSC

Henriksen et al, 2014

Liver-Gut Axis

• The liver continuously receives blood coming from

the intestines

• Carries bacterial products, toxins, nutrition

• Abnormalities in the intestine might trigger

inflammation in the liver

– Abnormal composition of the microbiome

(organisms living in the intestines)

– Are these bacteria causing PSC or responding

to the different cause?

Homing of Intestinal Lymphocytes to the PSC Liver

Olsson, Gastroenterology 1991; Loftus, Gut 2005Broome, Semin Liver Dis 2006; Mendes F, AJG 2007; Floreani et al, unpublished

PSC

PSC+IBD

IBD in PSC: 48-86%

IBD

IBD+PSC

PSC in IBD: 2.4-7.5%

PSC and IBD

International PSC Study Group

PATIENT AGE, SEX, AND INFLAMMATORY BOWEL DISEASE

PHENOTYPE ASSOCIATE WITH COURSE OF PRIMARY

SCLEROSING CHOLANGITIS

T.J. Weismüller1,2, J.A. Talwalkar3, C.Y. Ponsioen4, D.N. Gotthardt5, H.-U. Marschall6, S. Naess7, K. Holm7, R.K. Weersma8, K.N. Lazaridis3, J.

Fevery9, P.J. Trivedi10, C. Schramm11, O. Chazouilleres12, T. Müller13, M. Farkkila14, S. Almer15,16, S. Pereira17, A.L. Mason18, A. Floreani19, P.

Milkiewicz20, C. Levy32, H. Harley21, A. Pares22, L. de Vries4, C.N. Manser23, D. Huynh21, E. Rauws4, G. Dalekos24, N. Gatselis24, C. Berg25, H. Lenzen2,

M. Benito de Valle6, M. Imam3, G. Kirchner26, P. de Leuw27, V. Zimmer28, L. Fabris19, F. Braun29, P.L. Jansen4, G.M. Hirschfield10, M. Marzioni30, P.

Invernizzi31, B.D. Juran3, C.P. Strassburg1,2, U. Beuers4, M.P. Manns2, E. Schrumpf7, T.H. Karlsen7, A. Bergquist16, K.M. Boberg7

International PSC Study Group

1Department of Internal Medicine 1, University of Bonn, Bonn, Germany 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover

Medical School, Hannover, Germany, 3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States, 4Department of

Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands, 5Department of Internal Medicine, University Hospital of

Heidelberg, Heidelberg, Germany, 6Department of Molecular and Clinical Medicine, Sahlgrenska Academy,University of Gothenburg, Gothenburg,

Sweden, 7Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway, 8Department of Gastroenterology and Hepatology,

University Medical Center Groningen and University of Groningen, Groningen, Netherlands, 9Department of Hepatology, University Hospital

Gasthuisberg, Leuven, Belgium, 10NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United

Kingdom, 111st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 12Service d'Hépatologie, Hôpital Saint

Antoine, Assistance Publique-Hôpitaux de Paris,Faculté de Médecine Pierre et Marie Curie, Paris, France, 13Department of Internal Medicine,

Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany, 14Division of Gastroenterology, Department of Medicine,

Helsinki University Central Hospital, Helsinki, Finland, 15Gastroenterology & Hepatology, Linköping University, Linköping, 16Division of

Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden, 17UCL Institute for Liver and

Digestive Health, London, United Kingdom, 18Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada,

19Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy, 20Liver Unit and Liver Research

Laboratories, Pomeranian Medical University, Szczecin, Poland, 21Department of Gastroenterology and Hepatology, Royal Adelaide Hospital,

Adelaide, SA, Australia, 22Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain, 23Division for Gastroenterology and Hepatology,

University Hospital Zurich (USZ), Zürich, Switzerland, 24Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of

Larissa, University of Thessaly, Larissa, Greece, 25Department of Gastroenterology, Hepatology, and Infectiology, Medical Clinic, University of

Tübingen, Tübingen, 26Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, 27Department of Internal Medicine 1,

Johann Wolfgang Goethe-University Hospital, Frankfurt, 28Saarland University Medical Center, Homburg, 29UKSH, Campus Kiel, Kiel, Germany,

30Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy, 31 Center for Aotoimmune Liver Diseases, Humaitis Clinical and

Research Center, Rozzano (MI), Italy, 32Center for Liver Diseases University of Miami, Miami, Florida, United States

Gastroenterology, 2017

• International, Multicenter, Retrospective, Observational Study

• Inclusion criteria:

– all patients diagnosed between 1/1/1980 and 12/31/2010 with one of the following diagnoses:

• PSC

• small-duct-PSC

• PSC with features of AIH

• PSC with features of IgG4-assoc. cholangitis

• Exclusion criteria: secondary causes of sclerosing cholangitis

Study design

Gastroenterology, 2017

• 25 Parameters:

- demographic data: date of birth, gender, date of death/last follow-up, liver-tx

- PSC: date of main diagnosis, subtype of PSC, IgG4

- IBD: date of diagnosis, subtype of IBD (MC/CU/Ind. Col.), date of colectomy,

indication for colectomy

- malignancy: colorectal malignancy, hepatobiliary malignancy (CCA, GBC,

HCC, pancreatic carcinoma)

• Endpoints: overall-survival, transplant-free survival, malignancy-free survival

• Statistics: Mann-Whitney-U-Test, Kaplan-Meier, log-rank, Cox Regression

Study design

Gastroenterology, 2017

Gastroenterology, 2017

North America

Edmonton

Miami

Rochester

Western Europe

Amsterdam

Birmingham

Groningen

Leuven

London

Paris

Southern Europe

Ancona

Barcelona

Larissa

Milano

Padua

Australia

Adelaide

Northern Europe

Gothenburg

Helsinki

Linköping

Oslo

Stockholm

Central Europe

Berlin

Bonn

Frankfurt

Hamburg

Hannover

Heidelberg

Homburg

Kiel

Regensburg

Szczecin

Tübingen

Zürich

Gastroenterology, 2017

20,0%

24,6%

20,4%

2,3%

32,2%

0,5%

Gastroenterology, 2017

Results

» Data on 8212 patients submitted

» after exclusion of patients who did

not meet the inclusion criteria or

had insufficient follow-up

information 7121 patients remained

» Mean follow-up time: 21 years

Pancreatic Ca: 0.2%

0 2 4 6 10 15 20 25

Years after 1st diagnosis PSC

CCA Incidence

Gastroenterology, 2017

Results

Gastroenterology, 2017

• better overall survival in women than men and lower hepatobil. malignancy rate in women than men

Gender at diagnosis PSC

Gastroenterology, 2017

• 37.8% of all hepato-biliary malignancies occurred in the first year of PSC diagnosis, with the vast majority being CCA

Cumulative incidence of clinical events

Gastroenterology, 2017

• Survival decreases with advancing age

• The cumulative incidence of hepato-biliary malignancies increases with advancing age

Age

Gastroenterology, 2017

• Better overall survival and lower hepatobil. malignancy rate in patients with small-duct PSC

• Mean age at dg PSC: sdPSC 39years, PSC 41years(p=0.064)

Small-duct disease, and AIH/PSC vs. classical PSC

Gastroenterology, 2017

• Lower overall survival and higher hepatobil. malignancy rate in patients with IBD + PSC – but not significant

• Mean age at dg PSC: PSC+IBD 38.6years, PSC 44.3years(p<0.001)

IBD

Gastroenterology, 2017

Risk factors – multivariate Cox regression analysis

Gastroenterology, 2017

Characteristics of PSC-IBD compared with IBD alone

Biliary

content

Inflammation Fibrosis Cancer

Therapeutic targets in PSC

Low dose UDCA* vs mod dose UDCA** Survival free

of liver tranplantation

*Lindor et al, NEJM 1997

**Olsson J Hepatol 2004

Death/Tranplantation:

7.2% UDCA vs 10.9% placebo

(ns)

Summary on high dose-UDCA in PSC

Cullen et al, 2008 Lindor, Hepatology 2009

High dose UDCA trial

*Lindor et al, Hepatology 2009

In adult patients with PSC, we recommend

against the use of UDCA (1A). AASLD

Guidelines 2010

UDCA Withdrawal Causes Deterioration of Liver

Biochemistry and Symptoms in PSC

ALP GGT Bili

ALT AST

Parameters assessed

before and 3 months

after UDCA withdrawal

• 42% of patients reported increased pruritus

• Short term markers of quality of life were unaffected

Wunsch et al, Hepatologt 2014; 60: 931

Specific Medical Therapy for PSC

-The Past

Immunosuppressants

Prednisolone

Budesonide

Azathioprine

Cyclosporine

Tacrolimus

Methotrexate

Anti-TNF

Antifibrotics Colchicine

Antibiotics metronidazole

Vancomycin

rifaximin

Miscellaneous

Nicotine

Silymarine

Perfenidone

Probiotics

Results disappointing!

Potential Pathogenic Factors and

Targets for Treatment in PSC

• Gut microbiota

• Gut permeability

• Bacterial translocation

• Mucosal healing

• Bile formation

• Bile acid metabolism

• Cholangiocyte injury

• Bile duct integrity

Inflammation and fibrosis

Potential Molecular targets

Fickert J Hepatol 2014

1. Bile acid transporters

2. Nuclear receptors

3. Adhesion molecules

4. Cytokines/Chemokines

1

1

1

2

2

34

Antibiotics in PSC

*De Vries Liver Int 2016

Modulation of Gut Microbiota

Modulation of Gut Microbiota

Intestinal mucosal vessels

Natalizumab

Vedolizumab

Etrolizumab

Trivedi J Autoimmun 2013

Gut-tropic

T-cell

CCR9

a4b7

CCL25MAdCAM-1

Hepatic sinusoids

BT1023 PF00547659

PF00547659

MAdCAM-1VAP-1

CCL25

VAP-1 H2O2 NfkB MAdCAM-1

Vedolizumab in PSC

• 27 pts with PSC-IBD

• Vedo 300 mg iv at weeks 0, 2, 6

• Primary endpoint 50% reduction in ALP

• 63% achieved primary endpoint

Eksteen et al. PS124 ILC 2016

HC O 3-

C l-

CF

TR

CaC

l

C l-

C l-

S ecretinAC h

ATP

ATP

P2Y AE

2

Ins P 3

Ins P 3E R

C a++

c AMP

TGR-5

+

C a++

+

P2Y

AT

P

C l-

C l-C l

-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3-

HCO3- HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-HCO3

-HCO3

-

HCO3-

HCO3-

HCO3-

HCO3-

M3R

OHHO

COOH

OHHO

COO-

HCO3- H2CO3

Apoptos is

F ibros ing / s cleros ing cholangitis

C DC A

B ile

C holang ioc yte

HC O 3

-

H 2O + C O 2

+ H+

S R

C A

norUDCA: potent stimulus of biliary HCO3- secretion

Bile

norUDCA

Hofmann et al., Hepatology 2005;42:1391

Fickert et al., Gastroenterology 2006;130:465

Denk et al., Hepatology 2010;52:1758

Apoptosis

Senescence

Fibrosing

cholangiopathy

norUDCA in PSC – Phase II RCT

norUDCA 500 mg/d

Placebo

W2 W60

Baselin

e

W4

UDCA naïve

Or

Following 8nwks

UDCA Washout

norUDCA 1500 mg/d

W8 w16W8 W12

EOT

Follow-up

Screening

norUDCA 1000 mg/d

Fickert P et al J Hepatol 2017

norUDCA in PSC – Phase II RCT

Fickert P et al J Hepatol 2017

GENETI

C

&

OTHER

RISK

FACTOR

S

INNATE

IMMUNIT

Y

PAMP

M

infiltratio

n

TLRs on

BE

ADAPTATIV

E

IMMUNITY

Oligoclonal

Expansion

Th1

response

Aberrant

Homing

BILIARY

FIBROSIS

Portal

Fibroblast

Activation

LOXL2

TOXIC

BILE

BA/PL ratio

MDR3,

CFTR,

TGR5, SXR

Altered

Bile flow

PSC

Vancomycin

Rifaximin

Metronidazole

Minocycline

Tetracycline

Vedolizumab

Anti VAP-1

GSK1605786

Cyclosporine

Infliximab

Glucocorticoids

Sintuzumab

Tak-441

UDCA

nor-UDCA

atRA

Obeticolic acid

INT-777

Future? ?Combination Therapy in early, high risk patients

i. antibiotics, ii. Bile acid iii. Immune modulator

New Therapeutic Strategies for PSC