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