1. Long term outcome of patients with autoimmune hepatitis receiving mycophenolate mofetil (MMF) as first line treatment
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.

2. 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 1973
Krawitt EL, N Engl J Med 2006
Zachou, Aliment Pharmacol & Ther 2013
Van Gerven, J Hepatol 2013
Gatselis, WJG 2014

3. Autoantibody classification of AIH
ANA
SMA
ANCA
anti - ASGP-R
anti - SLA/LP
AIH-2
anti - LKM-1
anti - LKM-3
anti - LC-1
anti - ASGP-R
Dalekos, Eur J Intern Med 2002
Krawitt, N Engl J Med 2006
Bogdanos, Curr Med Chem2008
Czaja, Gastroenterology 2010
Zachou, Aliment Pharmacol Ther 2013

4. AIH - IIF
anti-LKM-1
ANA
SMA
anti-LC-1
AIH-type 1
AIH-type 2

5. 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).
Introduction
However 20% of patients have either side-effects or do not respond to treatment.
In addition, relapse after treatment withdrawal is almost universal.
Murray-Lyon IM, Lancet 1973
Krawitt EL, N Engl J Med 2006
Zachou, Aliment Pharmacol & Ther 2013
Van Gerven, J Hepatol 2013
Gatselis, WJG 2014

6. 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 2000
Chatur N, Liver Int 2005
Iaccarino L, Autoimmunity Reviews 2007
Inductivo-Yu I, Clin Gastroenterol Hepatol 2007
Hennes EM, Am J Gastroenterol 2008
Wolf 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

7. Aim of the study
To investigate the long term outcome of patients with AIH receiving MMF, especially after treatment withdrawal.

8. 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.

9. 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

10. Results 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.
p<0.001

11. 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

12. Characteristics of AIH patients who received MMF as front-line therapy according to response to treatment.
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)*
0.034
Time to diagnosis (months)
24.5 ± 44.4
36.6 ± 50
24 ± 28.6 NS
Female
59 (75.6%)
17 (70.8%)
4 (57.1%)
Presentation
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
0.046
Disease duration (months)
98.7 ± 67
116 ± 73.6
136 ± 53
AIH score
Revised
Simplified
14.6 ± 3.6
6.5 ± 1
14 ± 3.4
6.2 ± 1.3
13.5 ± 4
6.4 ± 1.3
AST (U/L)
410 ± 548
292 ± 377
178 ± 127
AST (U.L) month 6 of treatment
27 ± 9.2&^
66 ± 100&
79 ± 102^
0.006
ALT (U/L)
519 ± 667
354 ± 795
287 ± 199
ALT (U/L) month 6 of treatment
28.6 ± 11&^
75 ± 102&
87 ± 103^
0.001
IgG (mg/dl)
2068 ± 912
2075 ± 819
2405 ± 538
γ-GT (U/L)
118 ± 121
147 ± 182
197 ± 184
Bil (mg/dl)
2.8 ± 3.9
3.7 ± 6.3
1.1 ± 0.3
Cirrhosis at presentation
15 (19.2%)
9 (37.5%)
2 (28.6%)
Liver histology 1st biopsy
Moderate-severe inflammation
Severe fibrosis-cirrhosis
n=68
48 (70.6%)
22 (32.4%)
n=23
20 (87%)
10 (43.5%)
n=7
5 (71.4%)
3 (42.9%)
Liver histology 2nd biopsy
n= 23
6 (26.1%)
4 (17.6%)
n=11
5 (45.5%)
4 (36.4%)
n=4
2 (50%)
1 (25%)
ALT on the 6th month (p< 0.001) and acute onset (p= 0.024) were independent factors of CR.

13. Results MMF treatment was withdrawn in 40/109 patients.
Duration of MMF treatment: 60 (12-132) months.
30/40 (75%) remained in remission for 24 (2-129) months.
10 patients relapsed in 5 (2-24) months.

14. Characteristics of 40 AIH patients who stopped receiving MMF as front-line therapy according to maintenance of remission.
Remission (n=30)
Relapse (n=10) p
Age at disease onset (years)
47 ± 16
40 ± 14 NS
Time to diagnosis (months)
33 ± 49
45 ± 45
Female
21 (70%)
9 (90%)
Presentation
Acute
Insidious
11 (36.7%)
19 (63.3%)
2 (20%)
8 (80%)
Disease duration till last follow up (months)
125 ± 63
163 ± 63
Treatment duration (months)
62 ± 24
36 ± 21
0.005
AIH score
Revised
Simplified
14.5 ± 4
6.4 ± 1.4
14 ± 4
6.1 ± 1.4
AST (U/L)
106 ( )
66 (35-271)
ALT (U/L)
176 ( )
79 (40-264)
0.012
IgG (mg/dl)
1871 ± 582
2118 ± 738
IgG month 6 (mg/ dl)
± 245
1515 ± 382
0.004
γ-GT (U/L)
95.4 ± 97.6
71 ± 81
Bil (mg/dl)
1.15 ( )
0.85 ( )
HLA typing
HLA DRB1*0301
HLA DRB1*0401
HLA DRB1*0701
HLA DRB1*13
HLA B8
HLA A1B8DRB1*0301
N= 25
10 (40%)
3 (12%)
4 (16%)
7 (28%)
5 (20%)
N= 8
2 (25%)
3 (37.5%)
1 (12.5%)
Cirrhosis at presentation
4 (13.3%)
4 (40%)
Liver histology 1st biopsy
Moderate-severe inflammation
Severe fibrosis-cirrhosis
n=29
19 (65.5%)
9 (31%)
n=9
7 (77.8%)
4 (44.4%)
Improvement of stage (2nd biopsy)
yes/no
n= 19
10/ 9
n= 6
0/ 6
0.051
CR vs Relapse during treatment
23/7
5/5

15. Factors associated with maintenance of remission
p= 0.005

16. Factors associated with maintenance of remission
p= 0.012
p= 0.004

17. Characteristics of 40 AIH patients who stopped receiving MMF as front-line therapy according to maintenance of remission.
Remission (n=30)
Relapse (n=10) p
Age at disease onset (years)
47 ± 16
40 ± 14 NS
Time to diagnosis (months)
33 ± 49
45 ± 45
Female
21 (70%)
9 (90%)
Presentation
Acute
Insidious
11 (36.7%)
19 (63.3%)
2 (20%)
8 (80%)
Disease duration till last follow up (months)
125 ± 63
163 ± 63
Treatment duration (months)
62 ± 24
36 ± 21
0.005
AIH score
Revised
Simplified
14.5 ± 4
6.4 ± 1.4
14 ± 4
6.1 ± 1.4
AST (U/L)
106 ( )
66 (35-271)
ALT (U/L)
176 ( )
79 (40-264)
0.012
IgG (mg/dl)
1871 ± 582
2118 ± 738
IgG month 6 (mg/ dl)
± 245
1515 ± 382
0.004
γ-GT (U/L)
95.4 ± 97.6
71 ± 81
Bil (mg/dl)
1.15 ( )
0.85 ( )
HLA typing
HLA DRB1*0301
HLA DRB1*0401
HLA DRB1*0701
HLA DRB1*13
HLA B8
HLA A1B8DRB1*0301
N= 25
10 (40%)
3 (12%)
4 (16%)
7 (28%)
5 (20%)
N= 8
2 (25%)
3 (37.5%)
1 (12.5%)
Cirrhosis at presentation
4 (13.3%)
4 (40%)
Liver histology 1st biopsy
Moderate-severe inflammation
Severe fibrosis-cirrhosis
n=29
19 (65.5%)
9 (31%)
n=9
7 (77.8%)
4 (44.4%)
Improvement of stage (2nd biopsy)
yes/no
n= 19
10/ 9
n= 6
0/ 6
0.051
CR vs Relapse during treatment
23/7
5/5
Treatment duration was independently associated with maintenance of remission (p= 0.05)

18. 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.