management and treatment failures in autoimmune hepatitis ... · cholestatic liver diseases tom...

Management and treatment failures in autoimmune hepatitis and

cholestatic liver diseases

Tom Hemming KarlsenOslo University Hospital, Norway

ASSA SAGES, August 8th, 2015

Best of EASL is a program supported by an unrestricted medical education grant by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc.

Autoimmune and cholestatic liver diseases

Autoimmune and cholestatic liver diseases

Mechanistic compartments and drugs

Bile acid therapy

Immuno-suppression/anti-fibrotics

Lymphocytetrafickingblockade

Antibiotics/prebiotics/probiotics

Biochemical and serological improvement/remission

Histological improvement/remission

Transplant-free survival

Relieve symptoms (e.g. pruritus, fatigue) and preserve QOL

Avoid side effects

Long-term treatment (decades)

Treat to what end-point?

Altogether <75 RCTs in AIH, PBC and PSC (IBD: >1,000)

AIH: >10-20% (~half insufficient response, ~half intolerant to drugs)

PBC: 25-50% (depending on criteria used)

PSC: 100% (?)

«Difficult-to-treat» or «difficult-to-study»?

Difficult to treat?

Altogether <75 RCTs in AIH, PBC and PSC (IBD: >1,000)

AIH: >10-20% (~half insufficient response, ~half intolerant to drugs)

PBC: 25-50% (depending on criteria used)

PSC: 100% (?)

«Difficult-to-treat» or «difficult-to-study»?

Difficult to treat?

Standard management in AIH

www.easl.eu*Treatment probably no longer indicated in decompensated, burn‐outcirrhosis, unless high inflammatory score on liver biopsy

Liver cirrhosis at presentation?

Subclinical disease preceding diagnosis 1/3 adults and 1/2 children cirrhosis at diagnosis Response in cirrhosis similar, but slower? Decompensated cirrhosis? (consider HAI)

Gronbaek et al., 2014

n=1,318

Induction regimens in AIH

EASL, 2015

Week Prednisolone (mg/day) Azathioprine (mg/day)1 60

(= 1 mg/kg body weight)

‐

2  50 ‐3  40 504 30 505 25 100*6 20 1007 + 8 15 1008 + 9 12.5 100From week 10  10 100

AASLD, 2010

Standard management in AIH

www.easl.eu

Treat to what end-point?

Luth et al., 2008Dhaliwal et al., 2015www.easl.eu

Biochemical remission: normalization of IgG and transaminases Histological remission: normal histology or HAI < 4 or equivalent

Treatment >3 years and >2 years following biochemical remission A liver biopsy should be considered prior to treatment withdrawal In patients with HAI>3, treatment should not be discontinued Surveillance continued life-long (frequently during first 12 months) 50-90% of the patients relapse (depending on observation time) If relapse occurs, life-long immunosuppression advisable

Withdrawal of treatment in AIH

Montano-Loza et al., 2007www.easl.eu

„Difficult-to-treat AIH“

www.easl.eu

DILI is underdiagnosed and important DILI incidence in Europe 14 / 100,000 (or higher!) DILI with a strong immunoallergic component mimicking AIH? AIH mimicking as DILI due to drug exposure in recent weeks and

spontaneous improvement after cessation of drug exposure? AIH triggered by an offending drug (DILI-induced AIH)?

DILI and alternative diagnoses

Suzuki et al., 2011www.easl.eu

www.easl.eu

„Difficult-to-treat AIH“

Incomplete response and intolerance

www.easl.eu

Intolerance to treatment Azathioprine: Prednisolone monotherapy? Mycophenolate? Prednisolone: Budesonide? Referral for individualized therapy

Incomplete response Consider diagnosis, concomitant liver disease? Consider compliance (e.g. 6TGN) Increasing the dose of azathioprine to 2 mg/kg/day? Referral for individualized therapy (e.g. CNI, infliximab) Complete response may not be attainable in some patients

Mycophenolate in AIH

Hennes et al., 2008

Tacrolimus and infliximab

Larsen et al., 2007Weiler-Normann et al., 2013

HA

IA

LT

Altogether <75 RCTs in AIH, PBC and PSC (IBD: >1,000)

AIH: >10-20% (~half insufficient response, ~half intolerant to drugs)

PBC: 25-50% (depending on criteria used)

PSC: 100% (?)

«Difficult-to-treat» or «difficult-to-study»?

Difficult to treat?

UDCA response in PBC

Barcelona (ALP 40% decrease or normalization) – 39%

Paris (ALP<3ULN, AST<2ULN, bilirubin<1mg/dl) – 39%

Rotterdam (bilirubin and albumin normalization) – 24%

Toronto (ALP <1.67ULN and/or bilirubin <1mg/dl) – 43%

Mayo (ALP<2ULN or bilirubin 1mg/dl) – 52%

New algorithms occurring regularly, in the CPG Barcelona/Paris

De Vries et al., 2015

UDCA response in PSC?

«Medical PSC» «Surgical PSC»

Reversibility vs. time of diagnosis

Mechanistic compartments and drugs

Bile acid therapy

Immuno-suppression/anti-fibrotics

Lymphocytetrafickingblockade

Antibiotics/prebiotics/probiotics

Mechanistic compartments and drugs

Bile acid therapy

Ursodeoxycholic acid (PBC, PSC?)

Nor-ursodeoxycholic acid (PSC? – NCT01755507 phase II)

Obeticholic acid [FXR] (PBC? - NCT01473524 phase III)

Bezafibrate [PPARα/PXR] (PBC? - NCT01654731 phase III)

Budesonide [GR/PXR] (PBC?)

UDCA therapy in PBC

- By most authorities considered standard care

EASL guidelines: yes, evidence at class II-2, level B1

AASLD guidelines: yes, evidence at class I, level A

Cochrane: no, 16 RCTs, 1,447 patients

Long-term only: yes, 7 RCTs, 6 long-term follow-up, 1,038 patients

- Response heterogeneity/suboptimal UDCA response (30-50%)

UDCA therapy in PSC

Karlsen et al., 2013

UDCA therapy in PSC

EASL: surrogate markers, yes, evidence at class I, level B1

EASL: clinical-end points, no, evidence at class III, level C2

AASLD: no, evidence at level A1

Cochrane: insufficient evidence, 8 RCTs, 592 patients

- “Chemoprevention”: EASL – high-risk groups? (II-III, C2)

AASLD – no (B1)

Obeticholic acid in PBC?

Trivedi et al., in pressHirschfield et al., 2015

Obeticholic acid in PSC?

Frank Schaap et al., 2014

Bezafibrate in PBC?

Reig et al. EASL 2015 (courtesy Albert Pares)

Bezafibrate in PBC?

Courtesy Albert Pares

Mechanistic compartments and drugs

Bile acid therapy

Immuno-suppression/anti-fibrotics

Lymphocytetrafickingblockade

Antibiotics/prebiotics/probiotics

Mechanistic compartments and drugs

Immuno-suppression/anti-fibrotics

Prednisolone: PBC and PSC with features of AIH

Prednisolone: IgG4 associated sclerosing cholangitis

Mechanistic compartments and drugs

Immuno-suppression/anti-fibrotics

Genetic findings, e.g. ustekinumab (failed in PBC)

Anti-fibrotics, e.g. anti-LOXL2 (PSC? - NCT01672853)

Mechanistic compartments and drugs

Immuno-suppression/anti-fibrotics

Peter Fickert, unpublished

Mechanistic compartments and drugs

Bile acid therapy

Immuno-suppression/anti-fibrotics

Lymphocytetrafickingblockade

Antibiotics/prebiotics/probiotics

Mechanistic compartments and drugs

Lymphocytetrafickingblockade

Vedolizumab - anti-α4β7 integrin (PSC, in planning)

anti-VAP1 (PSC, in planning)

Mechanistic compartments and drugs

Lymphocytetrafickingblockade

Mechanistic compartments and drugs

Bile acid therapy

Immuno-suppression/anti-fibrotics

Lymphocytetrafickingblockade

Antibiotics/prebiotics/probiotics

Mechanistic compartments and drugs

Antibiotics/prebiotics/probiotics

Prophylaxis on ERC (PSC), rotating (PSC, long term?)

Vancomycin, rifaximin (PSC? – ongoing phase I/II)

Proof-of-concept vs. clinical utility

Tabibian et al., 2013

Treating complications

Management of cholestatic pruritus

Beuers et al., 2014

Management of fatigue in PBC

Dave Jones, Newcastle, UK

Manage depression (antidepressants, psychotherapy)

Manage sleep disturbances

Manage sicca syndrome in concomitant Sjögren

¨Autonomic dysfunction (antihypertensives?, fluid support, stockings)

Evidence for medication poor (modafinil?, fludrocortisone?, midodrine?)

Day planning, energy management, exercise, diet, social structures

Fatigue should not serve as the sole indication for liver transplantation

Endoscopic therapy in PSC

www.easl.eu

Dominant bile duct strictures with significant cholestasis should be treatedwith biliary dilatation (II-2/B1)

Biliary stent insertion should be reserved for cases where dilatation and biliary drainage are unsatisfactory (III/C2) (?) – the DILSTENT trial

Prophylactic antibiotic coverage is recommended (III/C1)

Malignancy in PSC and transplantation

Bjøro and Schrumpf, 2004

Summary points

Poor knowledge base with very few proper RCTs «Difficulties» common (AIH 10-20%, PBC 20-50%, PSC ~100%?) Immunosuppressive regimens effective in AIH and features of AIH (less) Ursodeoxycholic acid standard of care in PBC Ursodeoxycholic acid no longer advised (but still used!) in PSC Many treatment trials on the horizon, first wave = proof-of-concept? Pruritus and fatigue poorly understood, need better approaches Endoscopy and liver transplantation remain key tools in management Further reading: www.easl.eu