Hepatic Autoantigens in APECED associated AIHhasld.org/images/gianhang/document/item_l179.pdfApplication of the 2010 AASLD criteria of remission 13 to a cohort of Italian patients

Prof. Dr. med. M.P. Manns Department of Gastroenterology, Hepatology and Endocrinology 11.04.2018

Department of Gastroenterology, Hepatology and

Endocrinology

(1) Obermayer-Straub et al. Gastroenterology 2001; 121:668.

Hepatic Autoantigens in APECED associated AIH


Alcoholic Cirrhosis

Hepatitis in APS1

Dihydralazine Hepatitis

Tienilic Acid Hepatitis

Halothane Hepatitis

Autoimmune Hepatitis

Chronic Hepatitis C

Chronic Hepatitis D

Gonadal Failure in APS1

Adrenal Failure in APS1

Addison Disease

CYP2C9

rCYP3A1 rCYP2C11

CYP2E1 CYP2D6

UGT1

CYP11 CYP17

P450s & UGTs

CYP21

Anticonvulsant Hepatitis

? in APS1

CYP2A6 CYP1A2

CYPs and UGTs : Targets for Immune Reactions

Manns and Obermayer, Hepatology, 2002


0

20

40

60

80

100

Pati

en

ts [

%]

Hepatitis

in APS1 AIH PBC PSC

Vogel et al., Hepatology 2001 Djilali-Saiah et al., Journal of Hepatology 2004

Frequency of Mutations in the AIRE Gene in Patients with AIH, PBS and PSC


AIRE Mutations May Account for a More Severe Clinical Course in Children with Autoimmune Liver Diseases

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Autoantibodies Anti LKM-1 Anti CYP450 SCC Anti CYP450 C17

Anti-LC-1

Anti LKM-1 Anti CYP-450 SCC Anti CYP450 C17

Anti LKM-1

Anti LC-1

Extrahepatic manifestation

Hypopara-thyroidism Addison‘s disease

Gastric atrophy

(after ALF)

Autoimmune Enteropathy

(after OLT)

Autoimmune Enteropathy Autoimmune Nephropathy

(before ALF)

None

None

AIRE analysis Homozygous Deletion

P398fsX448, Exon 10

Homozygous Finnish major

mutation R257X, Exon 6

Heterozygous Polymorphism

R441C, Exon 12

None None

Clinical course ALF- 3 y, Azathioprin + Steroids

Remission

ALF- 6 m, OLT, azathioprin,

Steroids, Tacrolimus AIH recurrence

Exitus letalis at 3.5 y

ALF- 2 y, Azathioprin, Steroids,

Cyclosporin A Remission

ALF- 8 m, OLT, Chronic rejection

OLT n° 2 hepatic artery

thrombosis Exitus letalis 3.5 y

ALF- 1 y Azathioprin,

Steroids, Cyclosporin A

Remission

Lankisch, Jaquemin et al., Journal of Pediatrics 2005


Challenges in the diagnosis of AIH

• Diagnostic criteria

• Scoring systems

• Role of Autoantibodies

• Histology

• Differential Diagnosis: DILI, Viral Hepatitis, APECED, etc


10

AASLD CPG: First Line Treatment of AIH (adults)

Monotherapy Combination Therapy

Prednisone Prednisone Azathioprine

(mg/ day) (mg/ day) USA (mg/ day) EU (mg/ kg/ day)

Week 1 60 30 50 1 - 2

Week 2 40 20 50 1 - 2

Week 3 30 15 50 1 – 2

Week 4 30 15 50 1 – 2

Maintenance-Therapy 20 and less 10 50 1 - 2

Reasons for Choice of Therapy

Cytopenia Thiopurinmethyl-transferase-Deficiency Pregnancy Tumors Therapy


Management of AIH in adults

Mieli-Vergani, G. et al. (2018) Autoimmune hepatitis

Nat. Rev. Dis. Primers doi:10.1038/nrdp.2018.17

Adapted with permission from European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J. Hepatol. 63, 971–1004 (2015), Elsevier.


12

Treatment of AIH: Endpoints

AASLD Clinical Practice Guidelines: Manns MP, et al. Hepatology. 2010 Jun;51(6):2193-213.

Endpoints Criteria Recommendations Remission Disappearance of clinical symptoms,

Normalization of aminotransferases (ALT, AST), bilirubin und -globulins Normal liver histology or inactive liver cirrhosis

Slow Reduction of steroids within 6 weeks Control of serum AST, ALT, total-bilirubin, and -globulins in 3-week intervals during and 3 months after withdrawal, then every 6 months for 2 years, then every year


13

Application of the 2010 AASLD criteria of remission to a cohort of Italian patients with autoimmune hepatitis

Muratori L et al, Hepatology (correspondence), 2010 | Muratori P et al, Journal of Hepatology, 2009

AIH

(n=163)

Remission n=119 (73%) [AASLD 2002]

Remission n=42 (26%) [AASLD 2010]

TREATMENT

Remission AIH (>60 months)

methyilprednisolone 2-4 mg/daily or every other day

N=89

65 (73%) ALT


Jones, Manns, Terracciano, Torbenson, Vierling, The Lancet GH, May 2018

• Endpoint: Normal ALT, normal IgG, normal histology

• When: after 6 months

• However, patients with normal ALT and IgG may still develop cirrhosis and have increased liver mortality (e.g. UK AIH cohort)

• Therefore: Is normal ALT still normal enough ?

Unmet Needs and New Models for Future Trials in Autoimmune Hepatitis


15

Second Line Therapy for AIH: Alternative Drugs

Safety (Intolerance) versus Efficacy


16

Frequency and Nature of Side Effects (Adults)


Prednisone-Related Side Effects Azathioprine-Related Side Effects

Type Frequency Type Frequency

Cosmetic (usually mild) Facial rounding, Weight gain, Dorsal hump striae, Hirsutism, Alopecia

Somatic (usually mild) Emotional Instability, Glucose intolerance, Cataract

80% (after 2 years)

Hematologic (mild) Cytopenia

46% (especially with

cirrhosis)

Somatic (severe) Osteopenia, Vertebral compression, Diabetes (brittle), Psychosis, Hypertension (labile)

13% (Treatment

ending)

Hematologic (severe) Leukopenia Thrombocytopenia

6% (Treatment

ending)

Inflammatory/Neoplastic Pancreatitis, Opportunistic infection, Malignancy

Rare Somatic (mild) Nausea, Emesis, Rash, Fever, Arthralgias

5%

Neoplastic 3%

(after 10 years) Hematologic /enteric Bone marrow failure, villous atrophy, Malabsorption

Rare

Teratogenic Rare (theoretical)


17

Decrease Of Steroid Specific Side Effects In Patients Switched From Prednisone To Budesonide (n=87)

Manns MP, et al. Gastroenterology 2010;139:1198-1206

40.2% N=35

18.4% n=16

0

10

20

30

40

50

Month 6 Month 12

Perc

ent

P


18

European AIH-BUC Pediatric Subanalysis

Woynarowski et al. J. Pediatrics 2013 *Two sample t-test (two-sided). # Paired t-test

Mean weight change at Months 6 and 12

46 pts in 5 Pediatric Centers

1.2 0.5

5.1

-2.8 -4

-2

0

2

4

6

Month 6 Month 12

Weig

ht change, kg

#P


19

Role of Budesonide

– Instead of Predniso(lo)ne to reduce side effects in combination with Azathioprine

• Induction of remission in risk patients for steroid specific side effects (SSSE)

• Long-term maintenance of remission

– Approved for AIH in 23 European and 13 Non-European countries


Budesonide Versus Prednisone: Limitations

• Budesonide should not be given to cirrhotic patients due to

– Portal hypertension and loss of „topical effects“ – Potential safety issues (Hempfling et al, Hepatology, 2003)

• Long term benefits, i.e. on bone disease, are pending, long term studies are

needed – Peiseler et al, EASL-AASLD MTC AIH, 2015, Clin Gastroenterol Hepatol, 2018

• Limited if any benefit for patients not responding or dependent to

predniso(lo)ne – Lalanne et al, EASL – AASLD AIH MTC, London, 2015

EDITORIAL: The right drug at the right time for the right patient Manns, Jaeckel, Taubert, Clin Gastroenterol Hepatol, 2018


EFFICACY OF BUDESONIDE FOR THE LONG-TERM TREATMENT OF AUTOIMMUNE HEPATITIS IN A SINGLE CENTRE EXPERIENCE

Peiseler et al, EASL - AASLD AIH MTC, London, 2015, abstract book, p 70; Clin Gastro Hep 2018

0

20

40

60

80

100

6 months 24 months

% n

orm

aliz

ation

of

tra

nsam

inases

• Single Center Study (Hamburg/Germany)

• 83 Patients – 66 AIH, 17 AIH-Overlap

0

5

10

15

20

25

# o

f p

atien

ts

24 mths. budesonide

Worsened

Stable

Improved

10%

38%

35%

Initial Tx.

Prednisolone dependency

Steroid sp. side effects

0

20

40

60

80

100

Bud

eson

ide a

dhe

ren

ce

Last follow-up

Return to prednisolone

On budesonide


BUDESONIDE IN THE TREATMENT OF EXPERIENCED AUTOIMMUNE HEPATITIS PATIENTS WHO RELAPSED WHILE ON PREDNISONE AND/OR AZATHIOPRINE: FROM TRIALS TO EVERYDAY PRACTICE

© 2017 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG 22

Lalanne et al, EASL - AASLD AIH MTC, London, 2015 , abstract book, p 71 - 72

• Retrospective Single Center Study (Bologna/Italy)

• AIH reactivation under Prednisolone +/- Azathioprine with side effects contraindicated an increase of dose (19 out of 327 patients)

• Regimen:

• 14/19 patients: 9mg Budesonide + 50mg Azathioprine until remission, then taper to 6mg

• 5/19 patients: Budesonide monotherapy due to Azathioprine intolerance/side effects

Treatment response (Transaminases and IgG)

Remission 37%

Incomplete/non Response 63%

Nonresponders: Switched to Prednisolone within 7 month (1-60)


23 Frequency and Nature of Side Effects (Adults)


Prednisone-Related Side Effects Azathioprine-Related Side Effects

Type Frequency Type Frequency

Cosmetic (usually mild) Facial rounding, Weight gain, Dorsal hump striae, Hirsutism, Alopecia

Somatic (usually mild) Emotional Instability, Glukose intolerance, Cataract

80% (after 2 years)

Hematologic (mild) Cytopenia

46% (especially with

cirrhosis)

Somatic (severe) Osteopenia, Vertebral compression, Diabetes (brittle), Psychosis, Hypertension (labile)

13% (Treatment

ending)

Hematologic (severe) Leukopenia Thrombocytopenia

6% (Treatment

ending)

Inflammatory/Neoplastic Pancreatitis, Opportunistic infection, Malignancy

Rare Somatic (mild) Nausea, Emesis, Rash, Fever, Arthralgias

5%

Neoplastic 3%

(after 10 years) Hämatologic /enteric Bone marrow failure, villous atrophy, Malabsorption

Rare

Teratogenic Rare (theoretical)

Routine assessment of thiopurine methyltransferase (IPMT) ?


24

Mycophenolate Mofetil (MMF) as Second Line Therapy – Retrospective Analysis

• MMF in n = 36 patients – n = 27 due to AZA intolerance – n = 09 due to AZA insufficiency

• Remission : < 2x ULN • Total Remission to MMF: 14/36 (38 %) • Remission in AZA intolerant pts: 12/28 (~ 43 %) • Remission in AZA failure pts: 02/08 (~ 25 %)

• MMF should be considered in AZA intolerant patients

Hennes et al, Am J Gastro, 2008


25

Mycophenolate induction therapy treatment naïve patients (first line)

Zachou et al, J Hepatol 2011;55 636–646

▪Gamma globuline


26 Second line in autoimmune hepatitis: 6-thioguanine

Van den Brand, de Boer, ….Drenth, Bouma, EASL 2017

6-TG was effective and clinically well tolerated as rescue treatment in 25 pts with AIH, previously non-responsive or intolerant to thiopurins (AZA, 6-MP)


27

Second Line Therapy for AIH: Alternative Drugs

Safety (Intolerance) versus Efficacy


28

Second Line Therapy for Treatment Failures:

Alternative Drugs

Dose Side effects

Cyclosporine A 3-5 mg/kg kg/qd hypertension renal insuffiency

Tacrolimus 3 mg bid (5 – 7 ng/ml)

hypertension renal insuffiency Diabetes, neuropathy

Mycophenolate Mofetil 750-1000 mg bid Diarrhea, leucopenia

6-thioguanine 20 mg/day

6-mercaptopurine 1.5 mg/kg/day

Methotrexate 10 mg per week

Cyclophosphamide 1-1.5 mg/kg/day Cystitits, leucopenia

Everolimus 0.75-1.5mg bid (3-6ng/ml)

Proteinuria, lipid disturbance, ulcera


29

Everolimus (mTOR Inhibitor) as Second Line Therapy Retrospective Analysis

• N=7 / steroid refractory

• 3/7 complete biochemical

response (BR)

• 4/7 incomplete biochemical

response (IR)

Ytting and Larsen, Scand J Gastroenterol 2015


30

Management of failures to standard of care

– Biologicals

• Anti TNF

• Anti CD 20 (Rituximab)

• Anti B cell and anti BAFF-R (VAY736)


31

Treatment of refractory AIH with anti-TNF

Weiler-Norman et al. J Hepatol 2013


32

Treatment of refractory AIH with anti-TNF

Weiler-Norman et al. J Hepatol 2013


33

Anti-TNF alpha may cause AIH

• Induction of AIH following TNF alpha antagonists: – Harada K et al. Clin Rheumatol 2008 AIH Exacerbation following Etanercept in patients with

rheumatoid arthritis

– Ozorio G et al. Med J Aust 2007 AIH following infliximab therapy of ankylosing spondylitis.

– Cravo M. BioDrugs 2010 AIH induced by Infliximab in a patient with Crohn‘s disease, no relapse after switch to adalimumab


Rituximab Treatment of AIH

PLoS ONE 6(10): e26358

Chimeric monoclonal antibody against B cell marker CD20

Rituximab


35 Rituximab response: case report Successful Treatment of Refractory Autoimmune Hepatitis with Rituximab

D'Agostino et al. Pediatrics 2013

Department of Gastroenterology, Hepatology and

Endocrinology


37

Rituximab in AIH Immunohistochemistry

Burak et al. Can J Gastroenterol. 2013; 27: 272 – 80.

A: anti CD 3 staining B: Fox P3 + staining at baseline C: Fox P3 + staining 48 weeks after starting rituximab


Rituximab treatment experience in patients with complicated type 1 autoimmune hepatitis in Europe and North America

Than et al, EASL 2018, J Hepatol, 68, S217-8, 2018

• 22 patients, retrospective analysis, UK, Canada Germany • Befere and 24 months after RTX • Reduction of Predniso(lo)ne and freedom of flares • Improvement of ALT, AST and sustained for 24 months, (p < 0.0010)

• ALT 167 IU/L to 32 IU/L (p< 0.001) • AST 127 IU/L to 29 IU/L • IgG 18.9 g/l to 13.2 g/L (p< 0.001)



Kaplan-Meier curve of freedom from flare-up following Rituximab therapy


42

Rituximab – Complications and Adverse Events

• Usually mild, infrequent:

– Infusion reactions, bacterial infections, neutropenia, anemia, rash, fever, diarrhea, reactivation of viral infections

• But include:

– Late onset neutropenia, rheumatic disease, HBV reactivation, activation of a latent polyoma virus (JC virus) with multifocal leucoencephalopathy


Molecular pathogenesis of autoimmune hepatitis

Manns et al., Journal of Hepatology, 2015

VAY736


VAY736: Anti-BAFF-R antibody with dual action 1) ADCC mediated B cell depletion; 2) Functional BAFF-R blockade

www.clinicaltrials.gov: NCT03217422

Rapid and profound B cell depletion | Prevention of BAFF-induced hardening of autoimmunity

BAFF-R blockade

BAFF

B

B

B cell depletion NK cells Kupffer cells Granulocytes

B

BAFF-R

B

VAY736

Persistence of pathogenic B cells

Differentiation into long-lived PC

1 2

http://www.clinicaltrials.gov/


45

AIH: Future Therapies

• Can we increase therapeutic response by strengthening

immunoregulation ?

• Anti CD 3

• Low dose IL-2

• Adoptive transfer of Tregs ?

Treg

Teff


Molecular pathogenesis of autoimmune hepatitis

Manns et al., Journal of Hepatology, 2015


Intrahepatic accumulation of Tregs in AIH

© 2017 AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES WWW.AASLD.ORG 47

PB LTx: protocol biopsy after liver Tx; ACR: acute cellular rejection after liver Tx (steroid sensitive portal hepatitis)

Hamburg cohort

Peiseler et al. 2012

Hannover cohort

Taubert et al. 2014


Low IL-2 in patients with incomplete remission and under steroid therapy (pAIH)

Diestelhorst … Manns … Jaeckel, Taubert; Plos One 2017 Diestelhorst … Manns … Jaeckel, Taubert; submitted

Serum IL-2

pAIH: pediatric AIH; pNAFLD: pediatric NAFLD; aAIH: adult AIH BR: subsequent biochemical remission; IR: subsequent incomplete response; LTX: subsequent need for liver transplantation


Therapies of AIH: The Reality (1)

• SOC: None of the drugs Pred +/- Aza underwent drug development program


Therapies of AIH: The Reality (1)


– SOC not optimal for all !

– „Complete response“ varies from 26 – 90 %

– Responders have increased liver related mortality

– Intensified therapy for normal ALT and IgG but histological activit y ?

– Some patients overtreated ?


Jones, Manns, Terracciano, Torbenson, Vierling, The Lancet GH, May 2018

Bottom Up versus Top Down Approach

• Identification of high risk patients pretreatment and starting with disease

modifying biological agents

• Unmet needs: biomarkers – Proteomic based serum activity markers – Transcriptomic based liver tissue markers – Non-invasive fibrosis markers

Unmet Needs and New Models for Future Trials in Autoimmune Hepatitis


Therapies of AIH: The Reality


• Non-Responder Therapie

– None of the therapies are approved

– Clinical observation: improvement of concomittant AIH, e.g. TNF, anti CD20, stem cell therapies

– Use of approved immunosuppressive agents from rheumatology or transplantation medicine


14 Studies Found For Autoimmune Hepatitis (Recruiting)

https://clinicaltrials.gov accessed April 2018.

https://clinicaltrials.gov/


54

Thank you for your attention

Hannover Medical School

Documents

Hepatic Autoantigens in APECED associated AIHhasld.org/images/gianhang/document/item_l179.pdfApplication of the 2010 AASLD criteria of remission 13 to a cohort of Italian patients