hepatobiliary manifestations of inflammatory …...2018/11/01 · inflammatory bowel disease is...

Gideon Hirschfield University of Toronto PSC-IBD Programme

@AutoImmuneLiver

Hepatobiliary manifestations of Inflammatory Bowel Disease

Toronto, November 2018

Disclosure of Conflict of Interest

Nature of relationship(s) Name of for-‐profit or not-‐for-‐profit organiza1on(s)

Descrip1on of rela1onship(s)

Any direct financial payments including receipt of honoraria

Intercept, Cymabay, GSK,

Novar5s

Scien5fic consultancy in the development of new drugs for

pa5ents with PBC

Membership on advisory boards or speakers’ bureaus

Intercept, Falk I have presented my own slides at CME mee5ngs with Industry

sponsorship

Funded grants or clinical trials Gilead Educa5onal grant to support opera5ng costs of UK-‐PSC, a na5onal observa5onal study

Patents on a drug, product or device

N/A N/A

All other investments or relationships that could be seen by a reasonable, well-

informed participant as having the potential to influence the content of the educational

activity

Intercept, Gilead, Novar5s, GSK, Falk, NGM Bio,

Cymabay

I have been the local study inves5gator of early stage

industry sponsored clinical trials in pa5ents with PBC and PSC.

I have a rela1onship with a for-‐profit and/or a not-‐for-‐profit organiza1on to disclose:

Competences CanMEDS x Medical Expert (As Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical

knowledge, clinical skills, and professional values in their provision of high-‐quality and safe pa5ent-‐centred care. Medical Expert is the central physician Role in the CanMEDS Framework and defines the physician’s clinical scope of prac5ce )

Communicator (As Communicators, physicians form rela5onships with pa5ents and their families* that facilitate the gathering and sharing of essen5al informa5on for effec5ve health care)

x Collaborator (As Collaborators, physicians work effec5vely with other health care professionals to provide safe, high-‐quality, pa5ent-‐centred care)

Leader (As Leaders, physicians engage with others to contribute to a vision of a high-‐quality health care system and take responsibility for the delivery of excellent pa5ent care through their ac5vi5es as clinicians, administrators, scholars, or teachers)

x Health Advocate (As Health Advocates, physicians contribute their exper5se and influence as they work with communi5es or pa5ent popula5ons to improve health. They work with those they serve to determine and understand needs, speak on behalf of others when required, and support the mobiliza5on of resources to effect change)

Scholar (As Scholars, physicians demonstrate a lifelong commitment to excellence in prac5ce through con5nuous learning and by teaching others, evalua5ng evidence, and contribu5ng to scholarship)

x Professional (As Professionals, physicians are commiXed to the health and well-‐being of individual pa5ents and society through ethical prac5ce, high personal standards of behaviour, accountability to the profession and society, physician-‐led regula5on, and maintenance of personal health)

At the end of this session, the participant will be able:

1.  To understand the breadth of hepatobiliary concerns seen in patients with IBD

2.  To appreciate the approaches to effective diagnosis and current management

3.  To recognize why PSC-IBD is a distinct entity necessitating development of a separate care pathway

4.  To be conversant in the latest trial opportunities for patients

Overview Related or Associated

•  Medica5on side effects –  Azathioprine –  Methotrexate

–  Biologics –  5-‐ASA

•  Disease Associa5on –  Sclerosing cholangi1s –  Autoimmune hepa55s –  Portal vein thrombosis/Budd-‐Chiari –  Nodular regenera5ve hyperplasia

Unrelated but relevant

•  Independent liver disease –  Hepa55s B and immunosuppression –  Hepa55s E –  Cirrhosis and portal hypertension –  NAFLD

Risk factors for liver injury are not rare

•  Age/Renal func5on

•  Alcohol

•  Obesity

•  Diabetes

•  Pre-‐exis1ng liver disease

•  Concomitant medica5ons e.g. Methotrexate, Azathioprine, an1-‐TNF

Non-‐invasive markers of fibrosis •  Alterna5ves to liver biopsy are aXrac5ve, not just to the Hepatologist

–  Serum markers

–  Transient elastography •  BUT it is just a number; beware the report that implies it is something it isn’t!

•  Never use it as an absolute classifier of fibrosis or steatosis •  use it as an ADJUNCT to your care plan

PSC-‐IBD Programme: A challenge and an opportunity Synopses •  Fluctua5ng coli5s/Early PSC •  Ac5ve IBD on Vedolizumab in pa5ent with

cirrhosis and portal hypertension (Fibroscan >50kPa)

•  Recurrent cholangi5s secondary to stricturing PSC (rota5ng an5bio5cs)

•  New presenta5on of PSC-‐IBD (hepa55c with coli5s)

•  PSC on transplant wai5ng list •  Advanced cirrho5c PSC in pa5ent ini5ally

with ASC/IBD •  Progressive biliary changes on MRI (normal

LFTs) •  Asymptoma5c PSC with ALP >2.5xULN •  Symptoma5c PSC with coli5s ?up 5trate to

biologic •  Dukes C CRC post-‐OLT •  Symptoma5c recurrent PSC in liver grad(s)

Demographics •  All ages; whole families

•  Men and women

•  Pan-‐ethnicity

•  From mild to end-‐stage disease •  Pre-‐ and post-‐ transplant

•  Benign and malignant disease

•  Co-‐existent extra-‐hepa5c manifesta5ons

Sclerosing cholangitis- one black box in GI Medicine

Chronic bile duct disease leading to fibrotic strictures and saccular dilatations of the intra- and extrahepatic bile ducts

Nature Reviews Gastroenterology & Hepatology 14, 279–295 (2017)

Ulcerative C(h)ol(ang)itis

How many new pa1ents get disease each year? •  PBC – 2.3 (2.2-‐2.4) cf. 0.3-‐5.8 •  PSC – 0.7 (0.6-‐0.7) cf. 0-‐1.3 •  AIH – 1.7 (1.6-‐1.8) cf. 1.68 (1.60 to 1.76) Denmark

–  cases/100,000/year from 1998-‐2015

•  cf. Mul1ple Sclerosis – 5.5 (5.1-‐5.9) and T2DM – 396 (394-‐398)

2000 2005 2010 20150

1

2

3

4

Year

Inci

denc

e (p

er 1

00,0

00/y

ear)

PBC

2000 2005 2010 20150.0

0.5

1.0

1.5

2.0

Year

Inci

denc

e (p

er 1

00,0

00/y

ear)

PSC

2000 2005 2010 20150

1

2

3

Year

Inci

denc

e (p

er 1

00,0

00/y

ear)

AIH

Boonstra, K., et al/.(2012). JHep, 56(5), 1181–1188; Alonso, A., et al., (2007) J. Neurology, 254(12), 1736–1741; Sharma, M., et al., (2017) BMJ Open, 6(1), e010210. "

Webb et al. CGH 2017

Patchy disease characterised by strictures, inflammation and malignancy risk

Hirschfield, Karlsen, Lindor, Adams. Lancet.

IPSCSG Clinical cohort

Weismueller, Trivedi et al. Gastro 2017

Nature Genetics 48, 510–518 (2016) “In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.”

Clin Liver Dis 20 (2016) 15–31

IBD and PSC outcomes

Weismueller, Trivedi et al. Gastro 2017

Evaluation


High dose UDCA vs. Placebo

HEPATOLOGY, Vol. 50, No. 3, 2009

Tipping point: stage and risk are different

Changes in LSM as es5mated by the linear mixed model

(A) as a func5on of 5me and ini5al stage of fibrosis

(B) as a single con5nuous process extrapolated from the means of progression rates.

Corpechot et al. Gastroenterology 2014

Stratification •  Stage (Fibroscan, ELF, MRI, Biopsy)

•  Severity and risk (Liver biochemistry)

•  Treatment (UDCA)

PSC-IBD has the 3C(onfounder)s •  Cholangitis: ALP goes up and down and up and down

–  key difference between ALP in PSC and PBC •  Cholangiocarcinoma: patient dies but therapy effective?

•  Colitis: quality of life declines at same time as liver settles; colitis activity and non-invasive markers of liver fibrosis

–  How do you stratify for IBD in recruitment?

BEC Injury and its response

Bile Acids Immunoregulation

Fibrosis

FXR/FGF19 axis?

Bile acid uptake inhibition?

Microbiome manipulation?

Immunomodulation/ Cell therapy?

Secretome inhibitors?

Anti-fibrotics? Epithelial protectants?

Cell recruitment & adhesion?

New Therapeutic Opportunities

Augment HCO3

- secretion?

PPARs?

Down-‐regula5on of AE2 sensi5zes cholangiocytes to

apopto5c insults

norUDCA Phase 2 Trauner et al. Relative Changes in ALP From Baseline to EOT (ITT)

-50

-40

-30

-20

-10

0

Cha

nge

in A

LP (%

)

PLACEBO (N=40)

NU 500mg (N=39)

NU 1000mg (N=41)

NU 1500mg (N=39)

p = 0.0029

p = 0.0003

p < 0.0001

+1.2%

-12.3%

-17.3%

-26%

Slide courtesy of Prof Trauner/Falk ILC 2016

Values (%) are means (SD)

The AESOP Trial (Kowdley et al 2017): A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of

Obeticholic Acid in Patients with Primary Sclerosing Cholangitis

VCAM-1 MAdCAM-1

α4β1

α4β7

CCR9

VCAM-1

α4β1

α4β7 MAdCAM-1

Endothelial cell Gut homing lymphocytes PSC Liver infiltrating lymphocytes

VAP-1R

VAP-1

VAP-1R

CCR9

CCL25 CCL25

The ADAMS hypothesis

Courtesy of Prof. D Adams

Williamson et al. IPSCSG Vedo study Change in ALP (x ULN#)

Wilcoxon analyses

#ULN = upper limit of normal

Mean +/-‐ SD shown on graphs

Baseli

ne

Day 42

Day 98

Last f

/u0

1

2

3

4

5

Timepoint on VDZ

ALP

xULN

ALP at different time points

2.02

2.252.38

2.55

Mean

Mean

MeanMean

*ns

ns

Change in ALT

Baseli

ne

Day 42

Day 98

Last f

/u0

50

100

150

200

Timepoint on VDZ

ALT

(IU

/L)

ALP at different time points

57.771.3

78.5 78.2Mean

MeanMeanMean

**

ns*

Baseli

ne

Day 42

Day 98

Last f

/u0

50

100

150

Timepoint on VDZ

AS

T (IU

/L)

AST at different time points

51.1 48.6 49.8

72.4

Mean

Mean

MeanMean

***

Change in AST

^if ALP ULN=220

Baseli

ne

Day 42

Day 98

Last f

/u0

10

20

30

40

5050

100

Timepoint on VDZ

Bili

rubi

n (u

mol

/L)

Bilirubin at different time points

16.3 17.2 17.5

29.5

Mean

Mean

MeanMean

***

ns

ns

Change in bilirubin

ns p > 0.05 * p ≤ 0.05 ** p ≤0.01 ***p ≤0.001

Efficacy and safety of simtuzumab for the treatment of primary sclerosing cholangitis: results of a phase 2b, dose-ranging,

randomized, placebo-controlled trial

Muir et al. 2017

NGM282 (FGF19 analogue): No Sustained Changes in ALP, GGT or Total Bilirubin

383 409

354 351 356 355

500

450

400

350

300

250

200

150

100

50

0

ALP (U

/L)

p= 0.78

p = 0.22

p = 0.73

Placebo (n=20) 1 mg (n=21) 3 mg (n=21)

UDCA use did not impact treatment response at W12

Mean ALP (U/L)

Baseline Week 12

Hirschfield et al. In Press

NGM282 Decrease Liver Transaminases Supporting an Improvement in Hepatic Inflammation

0

20

40

100

120

ALT (U

/L)

Baseline Week 12

0

20

40

80 60

60

80

100

AST (U

/L)

Baseline Week 12

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

Mean (SD) Absolute D at W12 p-‐value

Placebo -‐4.5 (31.6) 0.255

NGM282 1mg -‐2.8 (62.8) 0.409

NGM282 3mg -‐42.7 (74.5) < 0.001

Mean (SD) Absolute D at W12 p-‐value

Placebo -‐5.3 (25.6) 0.068

NGM282 1mg -‐11.2 (62.2) 0.974

NGM282 3mg -‐24.5 (50.2) < 0.001

Placebo (n=20) 1 mg (n=21) 3 mg (n=21) Placebo (n=20) 1 mg (n=21) 3 mg (n=21)


NGM282 Rapidly Decreases PRO-C3 Levels Supporting a Suppression of Fibrogenesis

26.1

26.7

24.2

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9 10 11 12

PRO-‐C3 (ng/mL)

Placebo (n=20) 1 mg (n=21) 3 mg (n=21)

Study Week

20.4 (18.5) p = 0.058

14.2 (29.5) p = 0.017

29.5 (21.6) p = 0.094


The microbiota is different in patients with PSC-IBD

•  Significant difference in

the composi5on of the

microbiota between

condi5ons, irrespec5ve

of biopsy site (p=0.001).

•  This was confirmed by

constrained ordina5on,

which resulted in clear

separa5on between the

three groups.

Qureshi et al. Gut 2016

Vancomycin or metronidazole in patients with primary sclerosing cholangitis

Alimentary Pharmacology & Therapeu1cs 2013 pages 604-‐612, 5 FEB 2013 DOI: 10.1111/apt.12232

VANCOMYCIN

METRONIDAZOLE

*


*

*

*


Beyond the liver

•  Fa5gue

•  Pruritus

•  Concurrent autoimmune diseases

•  Reduced bone density

•  Abdominal pain

•  Complica5ons of IBD/Pouch

PSC can range from asymptoma1c and slowly progressive to symptoma1c and rapidly evolving.

Adapted from original slide of Kris Kowdley

Hepatology 2018

University of Toronto PSC-‐IBD Programme

hepatobiliary manifestations of inflammatory …...2018/11/01 · inflammatory bowel disease is...

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