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![Page 1: Kalliopi Zachou 1, Nikolaos Gatselis 1, Stella Gabeta 1, Asterios Saitis 1, George Koukoulis 2, George N. Dalekos 1 1 Department of Medicine and Research.](https://reader035.fdocuments.in/reader035/viewer/2022062407/56649dc95503460f94abeae8/html5/thumbnails/1.jpg)
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
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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
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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
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AIH - IIF
ANA
SMA
anti-LKM-1
anti-LC-1
AIH-type 1 AIH-type 2
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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
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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
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Aim of the study
• To investigate the long term outcome of patients with
AIH receiving MMF,
especially after treatment withdrawal.
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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.
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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
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• 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
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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
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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.
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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.
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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.
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Factors associated with maintenance of remission
p= 0.005
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Factors associated with maintenance of remission
p= 0.012 p= 0.004
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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)
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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.
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