Jonathan Potts PhD MRCPConsultant Hepatologist & HPB Endoscopist

jonathan.potts@nhs.net @PBEndoscopist

Hepato Pernambuco

13th July 2021

Sheila Sherlock Liver Centre, Royal Free & UCL Institute Of Liver & Digestive Health

Primary Sclerosing CholangitisOptimal management

OutlineOptimal PSC management

• Overview of PSC

- definition, diagnosis & natural history

• Current treatments

- Symptomatic, disease modifying

- ERCP

- Liver transplantation

• Patient experience in PSC

- symptom burden, psychological impact, unmet need

• Therapies under evaluation

• General management

• Cancer surveillance

PSC: Definition and prevalence

1. Karlsen TH, et al. J Hepatol 2017;67:1298–323;

ESGE/EASL CPG Endoscopy in PSC. J Hepatol 2017;66:1265–81

Image © Kari C Toverud CMI 2017

Chronic bile duct disease

• Multifocal bile duct strictures and progressive liver disease1

• IBD coexists in 70%

• Prevalence 1–16/100,000

• Regional differences across Europe

• More common in men

IBD phenotype

• Pan-UC with right-sided predominance

• Subtle ileal inflammation and rectal sparing are common

• Often more quiescent course

• Pouchitis more common

• Increased and unpredictable risk of biliary and colonic malignancy

Macroscopic bowel and bile duct pathology in PSC1

‘Backwash’

ileitis

Colonic

cancer

Pancolitis with

right-sided

predominance

Rectal sparing

Cholangiocarcinoma

Multifocal bile duct

strictures and dilatations

Diagnosis of PSC

- Unexplained cholestatic biochemistry

- Characteristic cholangiography

(MRCP superseded ERCP)

- multifocal strictures & segmental dilatations

- Secondary sclerosing cholangitis and other cholestatic disorders excluded.

EASL Cholestatic Liver Disease Guidelines J Hepatol 2009

PSC: Differential Diagnosis

PSC: Natural History

IPSCSG phenotype paper – 7,121 patients / 37 centres / 1980-2010

Male 65.5%, mean age of diagnosis 38 years, 70% with concomitant IBD

Weissmuller, Trivedi et al. Gastroenterology 2017

36.4%

Median survival 14.5 years

Event rate 5.1 per 100 patient years

Boonstra et al. Hepatology 2013

Medical managementTherapeutic Efficacy of UDCA in PSC

Beuers

(n=14)

Stiehl

(n=20)

Lindor

(n=105)

Mitchell

(n=26)

Olsson

(n=219)

Lindor

(n=150)

Dose

(mg/kg/d)

13-15 10-12 13-15 20 17-23 28-30

LFTs + + + + 0 +

Histology (+) (+) 0 +

ERCP/MRCP 0 0 -

Survival 0 0 -

Placebo Controlled Trials

Medical Management: UDCA• Early studies: biochemical improvement with 10-15mg/kg

• No improvement in outcomes/LT-free survival

• High dose (25-30mg/kg) terminated prematurely due to

increased incidence of SAEs, LT or death in UDCA group

• Stopping: associated with deterioration in biochemistry,

• no data on outcomes

Lindor 2009

Medical Management: immunosuppression

• No benefit in PSC from:

pred/aza/budesonide/CYA/methotrexate/MMF/anti-TNF

• PSC/AIH overlap:

• Compatible transaminases, IgG elevation & auto-abs

• Biopsy advised

• Treat dominant disease as per classical AIH

• AIH may evolve into PSC

• PSC with elevated IgG4 vs IgG4-SC1

• ?distinct, more aggressive clinical phenotype

• IgG4:1 ratio may help distinguish

• Immunosuppressant response not defined

1. Manganis WJG 2020

ERCP for Dominant Strictures in PSC:

What are the benefits?

Baluyut GIE 2001

63 PSC pts underwent

repeat therapeutic ERCP for

DS, median FU 34 mo

Gluck J Clin Gastroenterol 2008

106 PSC pts (84 with DS)

underwent 317 therapeutic

ERCPs, Mean FU 8 years

5-year survival:

Observed 83%

Predicted 65% p=0.03

4-year survival:

Observed 83%

Predicted 71% p=0.02

DILSTENT Study

Design: Prospective RCT of ERCP in PSC, 100 pts without

prior sphincterotomy, 9 European centres

Results: Stopped after interim analysis (65 patients)

recu

rre

nce fre

e p

ate

ncy o

f th

e s

tric

ture

Treatment-related AEs

17/65 (26%):

Pancreatitis 10/17

Cholangitis (4/17)

Stent (42%) v Dilatation (10%)

(OR=6.4, 95% CI 1.6–25.4).

Ponsioen et al. Gastroenterology 2018

2019 BSG guidelines on ERCP in PSC

Role of MDM: ERCP only after expert multidisciplinary

discussion (Strong recommendation / moderate evidence)

Antibiotic Prophylaxis for ERCP advised

(Strong recommendation / moderate evidence)

Role of Imaging: MRCP/liver MR +/- contrast CT to

evaluate (Strong recommendation / moderate evidence)

Tissue Sampling: Sampling of Dominant strictures

mandatory (Strong recommendation & evidence)

Choice of ERCP intervention: biliary dilatation preferred

to stenting (Strong recommendation / moderate evidence)

BSG 2019

Immune targets

Anti-fibrotics

Bile acid therapy

PSC: Targets for Treatment

PSC: Trials of New TherapiesBile Acid Manipulation

• Nor-URSO (Falk) – phase 3

• n=161, 12wks; 4wk f/u, dose dependent ALP

• Obeticholic Acid (FXR agonist; Intercept) – phase 2

• n=76, 24 wks, OCA 5-10mg ALP

• GS-9674 (non-steroidal FXR ag; Gilead) – phase 2

• n=52, 12 wks, dose dependent ALP

• NGM-282 (FGF19 analogue NGM Bio) – phase 2

• n=62, 12 wks, ALP, fibrosis biomarkers

Immune Modulation

• VAP-1 inhibitor (BTT1023; Birmingham) – phase 2

• Vedoluzimab (Takeda) – phase 2

• No biochemical signal in retrospective series

PSC: Symptoms & Patient Experience

Patient Survey: March 16

Most difficult part of living

with PSC (n = 340)

PSC: symptomatic & general management

Fatigue & Depression: Seek & treat alternative causes

Strong recommendation/low evidence

Pruritus:Cholestyramine (1st line) / Rifampicin/Naltrexone (2nd)

Weak recommendation/low evidence

Bone Disease: Osteoporosis assessment / treatment in all

Strong recommendation/moderate evidence

Nutrition: Empiric supplementation of fat-soluble vitamins

weak recommendation/moderate evidence

Other considerations:

Pregnancy

Support groups

BSG 2019

PSC: HPB Malignancy

IPSCSG phenotype paper (n=7,121)

Weissmuller & Trivedi Gastroenterology 2017

10.9%

21.6%

Cholangiocarcinoma

82% of malignancies

38% detected within 1st

year of diagnosis

Weissmuller, Trivedi et al. Gastroenterology 2017

PSC Management: CholangiocarcinomaRole of Ca 19-9: Routine measurement not advised

Weak recommendation / moderate evidence

Suspected CCA: specialist cancer MDT review essential

Strong recommendation / moderate evidence

Work-up: Contrast cross sectional imaging preferred

diagnostic/staging investigation

Confirmatory histology:

ERCP brush +/- FISH

Cholangioscopy

EUS-guided biopsy

Percutaneous bx

Strong recommendation / high evidence

BSG 2019

Investigation of suspected cholangioca

BSG 2019

PSC Management: Cancer Surveillance

Gallbladder Cancer: Annual surveillance ultrasonography

Intervention for polyps guided by cancer MDT

Weak recommendation / low evidence

HCC: surveillance as per cirrhosis guidelines

Weak recommendation / Low evidence

Colon Cancer: PSC-IBD annual surveillance colonoscopy

5 yearly / symptom lead if no IBD

Weak recommendation / very low evidence

BSG 2019

PSC: an excellent indication for OLTx

Risk adjusted transplant survival for adult

first elective transplantation; 2000-11

60

70

80

90

100

0 1 2 3 4 5

% 5 year survival HBV 86.9 PBC 83.0 PSC 79.5

33.9

26.9

25.1

21.6

21.1

15.4

12.4

5.8

0

10

20

30

40

Primarybiliary

cirrhosis

Sclerosingcholangitis

Cryptogeniccirrhosis

Autoimmunecirrhosis

Posthepatitis Bcirrhosis

Alcoholiccirrhosis

Posthepatitis Ccirrhosis

Cancer

Life

exp

ecta

ncy (

ye

ars

)

Primary liver disease

Overall 3.2 years lost

after OLT compared with

matched UK population

(26.0 v 29.2 years)

PSC: when to consider transplantation?

Journal of Hepatology 2017 vol. 67 j 1298–1323

Mayo PSC risk score: http://www.psc-literature.org/mrscalc.htm

UK-PSC risk score: http://www.uk-psc.com/resources/the-uk-psc-risk-scores/

OLT in PSC: Specific challenges

Referral

Assessment

&

Listing

TransplantPost-

transplant care

Patient Selection

Graft

Selection

Biliary

Anastomosis

Recurrent

PSC

Management of IBD

?transplantation for perihilar CCA

53% 5 year survival in Mayo series with neoadjuvant chemorad

Algorithm for PSC management

BSG 2019

The challenges of PSC in 2021….

Rare disease

• Few patients in mixed

GI practice

Unfavourable natural history

• <50% transplant free survival at 10 yrs

Patient experience

• Symptom burden

• Psychological impact

Lack of effective medical

therapy

• ‘Surgical’ management of

advanced disease

Complex disease

• Several phenotypes

• IBD Association (70%)

Young male patient

population

• Median age of

diagnosis <40yo

Weissmuller et al. Gastroenterology 2017

Boonstra et al. Hepatology 2013

Cancer risk

• Cholangiocarcinoma (>20% 20yr)

• Colorectal (10x higher risk than UC)

Thank you!

Questions?

Thanks to the RFH Team:Professor Doug Thorburn, Dr Aileen Marshall & Dr Beverley Kok

Dr Neil Halliday

Prof Alberto Quaglia, Dr Tu Vinh Luong, Dr Jen Watkins

Dr Neil Davies, Dr Dominic Yu, Dr Nick Woodward, Dr Anthie Papadopoulou

Transplant co-ordinators and research nursing staff