Kalliopi Zachou1, Nikolaos Gatselis1, Stella Gabeta1, Asterios Saitis1, George Koukoulis2, George N. Dalekos1

1 Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Thessaly, Greece, 2 Department of Pathology, Medical School, University of Thessaly, Larissa, Greece.

Long term outcome of patients with autoimmune hepatitis

receiving mycophenolate mofetil (MMF) as first line treatment

Introduction

Autoimmune Hepatitis (AIH) is a chronic liver disease of unknown etiology.

AIH is characterized by female predominance, hyperglobulinemia and

circulating autoantibodies (Abs) in the serum, interface hepatitis in liver

biopsy and a favorable response to immunosuppression.

Without treatment: 10-year survival 10%.

Standard treatment since the ’70s: corticosteroids ± azathioprine (ΑΖA).

Murray-Lyon, Lancet 1973Krawitt EL, N Engl J Med 2006

Zachou, Aliment Pharmacol & Ther 2013Van Gerven, J Hepatol 2013

Gatselis, WJG 2014

Autoantibody classification of AIH

AIH-1ANA

SMA

ANCA

anti - ASGP-R

anti - SLA/LP

AIH-2anti - LKM-1

anti - LKM-3

anti - LC-1

anti - ASGP-R

Dalekos, Eur J Intern Med 2002Krawitt, N Engl J Med 2006

Bogdanos, Curr Med Chem2008Czaja, Gastroenterology 2010

Zachou, Aliment Pharmacol Ther 2013

AIH - IIF

ANA

SMA

anti-LKM-1

anti-LC-1

AIH-type 1 AIH-type 2

Autoimmune Hepatitis (AIH) is a chronic liver disease of unknown etiology.

AIH is characterized by female predominance, hyperglobulinemia and circulating autoantibodies (Abs) in the serum, interface hepatitis in liver biopsy and a favorable response to immunosuppression.

AIH is a progressive disease leading to cirrhosis and need for liver transplantation.

Without treatment: 10-year survival 10%.

Standard treatment since the ’70s: corticosteroids ± azathioprine (ΑΖA).

Murray-Lyon IM, Lancet 1973Krawitt EL, N Engl J Med 2006

Zachou, Aliment Pharmacol & Ther 2013Van Gerven, J Hepatol 2013

Gatselis, WJG 2014

However 20% of patients have either side-effects or do not respond to treatment.

In addition, relapse after treatment withdrawal is almost universal.

Introduction

Introduction

The role of mycophenolate mofetil (MMF) as an alternative has been explored in several small retrospective studies, mainly in non-responders or in patients that did not tolerate the standard treatment.

Richardson PD, J Hepatol 2000Chatur N, Liver Int 2005

Iaccarino L, Autoimmunity Reviews 2007Inductivo-Yu I, Clin Gastroenterol Hepatol 2007

Hennes EM, Am J Gastroenterol 2008Wolf DC, Dig Dis Sci 2009

• We have recently shown that the use of MMF as first-line treatment results in high percentages of remission, fewer side-effects, early corticosteroid withdrawal and lack of non-response.

Zachou et al, J Hepatol 2011

Aim of the study

• To investigate the long term outcome of patients with

AIH receiving MMF,

especially after treatment withdrawal.

Patients

• 109 patients with well-defined AIH were included (2001-

2014).

• Follow up: 72 (3-168) months

• All patients received prednisolone (1mg/kg/d) and MMF

(1.5-2 g/d).

• Treatment withdrawal: after ≥ 4 years and complete

response for at least 2 years.

Response to treatment

• Complete Response (CR): AST, ALT and γ-globulin normalization,

disappearance of symptoms and minimal or no inflammation in liver biopsy.

• Partial Response (PR): partial decrease of AST/ALT<2xULN without achieving

complete normalization and inability to withdraw/taper corticosteroids.

• No Response (NR): persistently elevated AST/ALT>2xULN despite intensive

immunosuppresion and compliance.

• Response with relapses (RR): initial clinical and biochemical response followed

by a rise in AST/ALT>2xULN and/or reappearance of symptoms.

Manns, Hepatology 2010,Zachou, J Hepatol 2011

• 102/109 patients (93.6%) had initial CR.

• Aminotransferases and g-globulins normalized in 2 (1-18) months.

• 83/102 (81.3%) had CR within 3 months.

Results

p<0.001base-line

month 1

month 6

month 12

year 2 year 3 year 4 year 5 end of follow

up

0

50

100

150

200

250

300

350

400

450

500

mean AST IU/L

mean ALT IU/L

base-line

month 1

month 6

month 12

year 2 year 3 year 4 year 5 end of follow

up

0

500

1000

1500

2000

2500

mean IgG mg/dl

Results 78/109 patients (71.6%) had CR

• 61/78 remained in CR after cortiscosteroid withdrawal

(CR without corticosteroids)

24/109 (22%) had RR

initial CR followed by relapse during corticosteroid tapering

(corticosteroid-dependent CR)

7/109 (6.4%) had PR

No patient was non-responder

CR RR PR NR

n=78

n=24

n=7n=0

AIH patients with CR (n=78)

AIH patients with RR (n=24)

AIH patients with PR (n=7)

p

Age at disease onset (years) 48 (16-75)* 44 (12-70) 24 (14-53)* 0.034Time to diagnosis (months) 24.5 ± 44.4 36.6 ± 50 24 ± 28.6 NSFemale 59 (75.6%) 17 (70.8%) 4 (57.1%) NSPresentation Acute Insidious

33 (42.3%)**45 (57.7%)

5 (20.8%)19 (79.2%)

0**7 (100%)

0.021

Total follow up (months) 70 ± 45.6*** 91.5 ± 48*** 101 ± 28.5 0.046Disease duration (months) 98.7 ± 67 116 ± 73.6 136 ± 53 NSAIH score Revised Simplified

14.6 ± 3.66.5 ± 1

14 ± 3.46.2 ± 1.3

13.5 ± 46.4 ± 1.3

NSNS

AST (U/L) 410 ± 548 292 ± 377 178 ± 127 NSAST (U.L) month 6 of treatment 27 ± 9.2&^ 66 ± 100& 79 ± 102^ 0.006ALT (U/L) 519 ± 667 354 ± 795 287 ± 199 NSALT (U/L) month 6 of treatment 28.6 ± 11&^ 75 ± 102& 87 ± 103^ 0.001IgG (mg/dl) 2068 ± 912 2075 ± 819 2405 ± 538 NSγ-GT (U/L) 118 ± 121 147 ± 182 197 ± 184 NSBil (mg/dl) 2.8 ± 3.9 3.7 ± 6.3 1.1 ± 0.3 NSCirrhosis at presentation 15 (19.2%) 9 (37.5%) 2 (28.6%) NSLiver histology 1st biopsy

Moderate-severe inflammationSevere fibrosis-cirrhosis

n=6848 (70.6%)22 (32.4%)

n=2320 (87%)

10 (43.5%)

n=75 (71.4%)3 (42.9%)

NSNS

Liver histology 2nd biopsyModerate-severe inflammationSevere fibrosis-cirrhosis

n= 236 (26.1%)4 (17.6%)

n=115 (45.5%)4 (36.4%)

n=42 (50%)1 (25%)

NSNS

Characteristics of AIH patients who received MMF as front-line therapy according to response to treatment.

ALT on the 6th month (p< 0.001) and acute onset (p= 0.024) were independent factors of CR.

MMF treatment was withdrawn in 40/109 patients.

Duration of MMF treatment: 60 (12-132) months.

Results

Relapse

Remission

10

30

Maintenance of remission after MMF withdrawal

Number of patients

• 30/40 (75%) remained in remission for 24 (2-129)

months.

• 10 patients relapsed in 5 (2-24) months.

Remission (n=30) Relapse (n=10) pAge at disease onset (years) 47 ± 16 40 ± 14 NSTime to diagnosis (months) 33 ± 49 45 ± 45 NSFemale 21 (70%) 9 (90%) NSPresentation Acute Insidious

11 (36.7%)19 (63.3%)

2 (20%) 8 (80%)

NS

Disease duration till last follow up (months) 125 ± 63 163 ± 63 NSTreatment duration (months) 62 ± 24 36 ± 21 0.005AIH score Revised Simplified

14.5 ± 46.4 ± 1.4

14 ± 46.1 ± 1.4

NSNS

AST (U/L) 106 (21-3050) 66 (35-271) NSALT (U/L) 176 (11-3320) 79 (40-264) 0.012IgG (mg/dl) 1871 ± 582 2118 ± 738 NSIgG month 6 (mg/ dl) 1121.7 ± 245 1515 ± 382 0.004γ-GT (U/L) 95.4 ± 97.6 71 ± 81 NSBil (mg/dl) 1.15 (0.26-21.6) 0.85 (0.5-2.5) NSHLA typingHLA DRB1*0301 HLA DRB1*0401HLA DRB1*0701HLA DRB1*13HLA B8HLA A1B8DRB1*0301

N= 2510 (40%)3 (12%)4 (16%)7 (28%)7 (28%)5 (20%)

N= 82 (25%)

3 (37.5%)1 (12.5%)2 (25%)

1 (12.5%)0

NSNSNSNSNSNS

Cirrhosis at presentation 4 (13.3%) 4 (40%) NSLiver histology 1st biopsy

Moderate-severe inflammationSevere fibrosis-cirrhosis

n=2919 (65.5%)

9 (31%)

n=97 (77.8%)4 (44.4%)

NSNS

Improvement of stage (2nd biopsy)yes/no

n= 1910/ 9

n= 60/ 6 0.051

CR vs Relapse during treatment 23/7 5/5 NS

Characteristics of 40 AIH patients who stopped receiving MMF as front-line therapy according to maintenance of remission.

Factors associated with maintenance of remission

p= 0.005

Factors associated with maintenance of remission

p= 0.012 p= 0.004

Remission (n=30) Relapse (n=10) pAge at disease onset (years) 47 ± 16 40 ± 14 NSTime to diagnosis (months) 33 ± 49 45 ± 45 NSFemale 21 (70%) 9 (90%) NSPresentation Acute Insidious

11 (36.7%)19 (63.3%)

2 (20%) 8 (80%)

NS

Disease duration till last follow up (months) 125 ± 63 163 ± 63 NSTreatment duration (months) 62 ± 24 36 ± 21 0.005AIH score Revised Simplified

14.5 ± 46.4 ± 1.4

14 ± 46.1 ± 1.4

NSNS

AST (U/L) 106 (21-3050) 66 (35-271) NSALT (U/L) 176 (11-3320) 79 (40-264) 0.012IgG (mg/dl) 1871 ± 582 2118 ± 738 NSIgG month 6 (mg/ dl) 1121.7 ± 245 1515 ± 382 0.004γ-GT (U/L) 95.4 ± 97.6 71 ± 81 NSBil (mg/dl) 1.15 (0.26-21.6) 0.85 (0.5-2.5) NSHLA typingHLA DRB1*0301 HLA DRB1*0401HLA DRB1*0701HLA DRB1*13HLA B8HLA A1B8DRB1*0301

N= 2510 (40%)3 (12%)4 (16%)7 (28%)7 (28%)5 (20%)

N= 82 (25%)

3 (37.5%)1 (12.5%)2 (25%)

1 (12.5%)0

NSNSNSNSNSNS

Cirrhosis at presentation 4 (13.3%) 4 (40%) NSLiver histology 1st biopsy

Moderate-severe inflammationSevere fibrosis-cirrhosis

n=2919 (65.5%)

9 (31%)

n=97 (77.8%)4 (44.4%)

NSNS

Improvement of stage (2nd biopsy)yes/no

n= 1910/ 9

n= 60/ 6 0.051

CR vs Relapse during treatment 23/7 5/5 NS

Characteristics of 40 AIH patients who stopped receiving MMF as front-line therapy according to maintenance of remission.

Treatment duration was independently associated with maintenance of remission (p= 0.05)

Conclusions

• MMF is an efficient front-line treatment for AIH.

• MMF as first-line treatment in AIH achieved the highest

rates of maintenance of remission (75%) ever published.

• Since relapse after treatment withdrawal is almost

universal with conventional therapy, MMF could be an

important first-line regimen for AIH.