kalliopi zachou 1, nikolaos gatselis 1, stella gabeta 1, asterios saitis 1, george koukoulis 2,...
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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.