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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
Hirschfield, Karlsen, Lindor, Adams. Lancet.
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)
Hirschfield et al. In Press
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
Hirschfield et al. In Press
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
*
Hirschfield, Karlsen, Lindor, Adams. Lancet.
*
*
*
Hirschfield, Karlsen, Lindor, Adams. Lancet.
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
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