Systematic review of response criteria and endpoints in autoimmune hepatitis

by the International Autoimmune Hepatitis Group

Simon Pape, Romée JALM Snijders, Tom JG Gevers, Oliver Chazouilleres, George

N Dalekos, Gideon M Hirschfield, Marco Lenzi, Michael Trauner, Michael P Manns,

John M Vierling, Aldo J Montano-Loza, Ansgar W Lohse, Christoph Schramm, Joost

PH Drenth, Michael A Heneghan, on behalf of the International Autoimmune

Hepatitis Group (IAIHG) collaborators

Table of content
Figure 1: Flow chart.

Figure 2: Flow chart.

Table 1: Various published definitions for endpoints in AIH treatment 1970-2015

Table 2a: All survey questions and results from the first round

Table 2b: All survey questions and results from the second round

Supplementary Table 3: Calculation of the disagreement index, adapted from Lantinga et al.

Supplementary Table 4: Pubmed search strategy

Supplementary Table 5a: Baseline characteristics. Outcomes in study cohort: patient with treatment
response (≥50% decrease of serum transaminases within 4 weeks after initiation of treatment) vs.
patient without a treatment response (<50% decrease of serum transaminases within 4 weeks after
initiation of treatment).

Supplementary Table 5b: Baseline characteristics. Outcomes in study cohort: patients with CBR
(normalization of serum transaminases and IgG below the ULN, within 6 months after initiation of
treatment) vs. patients without CBR (no normalization of serum transaminases and IgG below the
ULN, within 6 months after initiation of treatment).
Supplementary Fig. 1: Flow chart. Patient are divided into two groups based on
their treatment response within 4 weeks. AIH, autoimmune hepatitis.

Supplementary Fig. 2: Flow chart. Patient are divided into two groups based on
complete biochemical response within 6 months. AIH, autoimmune hepatitis; CBR,
complete biochemical response.
Supplementary Table 1: various published definitions for endpoints in AIH treatment
1970-2015

Study Used endpoints with definitions

Clinical trials

Cook 1971 Change in serum bilirubin, albumin, globulin. Survival.

Soloway 1972 Remission: clinical normality, return to all customary activities,

and disappearance of histological signs of disease activity.

Total remission: achievement of biochemical normality (normal

AST, bilirubin, albumin and gamma-globulin).
Subtotal remission: mild abnormality of either AST or bilirubin.

Improvement: disappearance of ascites, if present, together with

decreases of AST to 33% and of gamma-globulin to 33% of
pretreatment levels.

Deterioration: development of ascites or bleeding varices, a 67%

increase in AST, or a 33% increase in gamma-globulin from
pretreatment levels.

Treatment failure: development of encephalopathy in the

absence of an exogenous precipitating factor; or increasing
ascites with a 2-fold increase in serum bilirubin.

Murray-Lyon 1973 Survival; cause of death. Change in bilirubin and gamma-

globulin.

Summerskill 1975 Remission: (1) absence of symptoms and return of the patient to
customary activities; (2) return of all liver function and
immunoserological tests to normal, apart from AST x 2 normal
and, in some instances, HBsAg; and (3) normal histological
appearances of the liver or features of inactive hepatitis with
portal tract inflammation, with or without minimal piecemeal
necrosis (appearances identical with those in chronic persistent
hepatitis).

Biochemical resolution: improvements in clinical and laboratory

features specified under (1) and (2) above without histological
verification of (3).

Relapse: AST > x 3 normal and the return of morphological

features of activity.

Treatment failure: the onset of endogenous coma, ascites, or

 elevation of serum bilirubin and AST at least 66 % above
previous values, or side-effects necessitating cessation of
medications.

Tage-Jensen 1982 Survival; cause of death. Changes in ANA/SMA titer.

Czaja 1993 Remission: absence of symptoms, decrease in the serum AST

level to less than twice normal, and improvement of other
standard liver tests (serum gamma-globulin and bilirubin levels)
to normal.

Treatment failure: worsening of symptoms or laboratory tests

during therapy.

Drug toxicity: intolerance of the medication.

Czaja 1999 Remission: absence of symptoms, decrease in the serum AST

level to less than twice normal, and improvement of other
standard liver tests (serum gamma-globulin and bilirubin levels)
to normal.

Treatment failure: clinical, laboratory, and/or histological

deterioration during corticosteroid treatment.

Repeated relapse: at least 2 exacerbations of disease after

corticosteroid-induced remission and drug withdrawal.

Incomplete response: clinical and laboratory improvement or

stability during corticosteroid therapy but failure to achieve a
sustained remission after protracted treatment.

Stern 1977 Changes in liver function tests (bilirubin, AST, albumin, gamma-
globulin, ceruloplasmin).

Drug toxicity: bleeding or perforated peptic ulcer, vertebral

collapse, diabetes requiring insulin, or psychosis.

Hegarty 1984 Remission: absence of symptoms, serum aminotransferase

(AST) concentrations within the normal range (<40 IU/l) on at
least four consecutive six monthly estimations, and liver histology
showing mild portal lymphocytic infiltration in the absence of
piecemeal necrosis.

Biochemical relapse: AST>240 IU/l.

Stellon 1985 Remission: serum AST of less than 40 IU/l on 4 consecutive 3-

monthly estimations.

Stellon 1988 Histological remission: no or only mild inflammatory activity

Manns 2010 Complete biochemical remission: serum ALT and AST within
normal range.

Complete response to therapy: complete biochemical remission

combined with absence of steroid-specific side-effects.

Meeting reports / guidelines

Johnson 1993 Complete response: marked improvement of symptoms and

IAIHG meeting report return of all liver test values completely to normal within 1 year
and sustained at least for a further 6 months on maintenance
therapy, or a liver biopsy showing minimal activity OR marked
improvement of symptoms together with at least 50%
improvement of liver function tests during the first month of
treatment, with ALT and AST levels twice ULN within 6 months or
a liver biopsy showing minimal activity.

Partial response: improvement of symptoms together with at

least 50% improvement of all liver test results during the first two
months of treatment with continuing decreases thereafter, but
with AST and ALT levels still not completely normal by 1 year OR
Improvement of symptoms and return of all liver test values to
normal within 6 months, but with a liver biopsy specimen still
showing continuing activity.

No response: either both of the following: liver test values sill

greater than 50% of presenting value after 1 month of treatment
or a liver biopsy showing no significant change in activity after 6
months OR greater than 50% improvement in liver test values
during the first one or two months but not becoming completely
normal and with no further improvement by six months.

Treatment failure: deterioration of patient’s condition despite

improvement in some parameters of disease activity.

Relapse: either both of the following: an increase in serum AST

and ALT levels of greater than twice the upper normal limit or a
liver biopsy specimen showing active disease, with or without
 reappearance of symptoms, after a “complete” response as
defined above OR reappearance of symptoms of sufficient
severity to require increased (or reintroduction of)
immunosuppression, accompanied by any increase in serum
AST and ALT levels, after a “complete” response as defined
above.

EASL guideline 2015 Biochemical remission: normalization of IgG and transaminases.

Histological remission: normal histology or minimal hepatitis (HAI

<4 or equivalent).

Treatment failure: without immediate severity: a lack of, or only

minimal, improvement in clinical and laboratory features after
several weeks of standard treatment but without liver failure.

With immediate severity: ‘acute severe AIH’: INR ≥1.5 without

cirrhosis

Insufficient response: occurrence of some improvement in

clinical, biochemical and histological parameters but without
reaching complete resolution.

AASLD guideline Remission: disappearance of symptoms, normal serum

2010 aminotransferases, bilirubin and gamma-globulin levels, normal
hepatic tissue or inactive cirrhosis.

Treatment failure: worsening clinical, laboratory, and histological

features despite compliance with therapy. Development of
jaundice, ascites or hepatic encephalopathy.

Incomplete response: some or no improvement in clinical,

laboratory, and histological features despite compliance with
therapy after 2-3 years. No worsening of condition.

BSG guideline 2014 Complete treatment response: normalization of either AST and
ALT as well as IgG.

CSH guideline 2015 Biochemical remission: normalization of ALT/AST and IgG/γ-

globulin.

Insufficient response: ALT/AST and/or IgG/γ-globulin improve but

still remain abnormal.
Supplementary Table 2a: all survey questions and results from the first round

Definition Item options Median Disagreement

rating index

Remission in AIH is normalization of serum

best defined as: transaminases below the upper 6 1.04
limit of normal (ULN)

normalization of serum
transaminases and serum IgG 8 0.02
below the ULN

liver histology with a Hepatitis

Activity Index (HAI) <4/18 or 8 0.32
equivalent

Remission in AIH 3 months after initiation of

3 0.65
should be obtained no treatment
later than:
6 months after initiation of
7 0.65
treatment

12 months after initiation of

8 0.37
treatment

18 months after initiation of

3 1.10
treatment

24 months after initiation of

2 1.55
treatment

Complete response in normalization of serum

AIH is best defined as: transaminases below the upper 6 1.29
limit of normal (ULN)

normalization of serum
transaminases and serum IgG 8 0.16
below the ULN

normalization of serum 7 0.65

transaminases, serum IgG
below the ULN, and reduction of
liver stiffness on repeated
examinations with transient
elastography
 >75% reduction of serum
1 0.29
transaminases

>50% reduction of serum

1 0.13
transaminases

>25% reduction in serum

1 0.06
transaminases

Insufficient response is <50% reduction of serum

5 1.70
best defined as: transaminases

persistence of elevated serum

6 0.52
transaminases > 2 times ULN

persistence of elevated serum

transaminases > 2 times ULN 7 0.65
and serum IgG > ULN

lack of complete response

(based on above-mentioned 8 0.13
definition)

increased liver stiffness on

repeated measurements with 4 0.65
transient elastography

Insufficient response 1 month after initiation of

2 0.29
should be determined treatment
no later than:
3 months after initiation of
4 0.65
treatment

6 months after initiation of

7 0.41
treatment

12 months after initiation of

8 0.51
treatment

Non-response in AIH is no improvement of serum

7 0.50
best defined as: transaminases

no improvement of serum
7 0.37
transaminases or serum IgG

no improvement of serum
6 0.65
transaminases, bilirubin and INR

persistent histological activity 5 1.06

 (HAI ≥4/18 or equivalent)

no improvement of serum
transaminases, serum IgG and
8 0.49
persistent histological activity
(HAI ≥4/18 or equivalent)

<25% reduction of serum

4 1.29
transaminases

<50% reduction of serum

3 0.65
transaminases

<75% reduction of serum

2 0.35
transaminases

development of signs of hepatic

5 1.53
decompensation

Non-response should 2 weeks after initiation of

3 0.65
be determined no later treatment
than:
4 weeks after initiation of
5 1.70
treatment

6 weeks after initiation of

4.5 1.49
treatment

8 weeks after initiation of

5 1.03
treatment

12 weeks after initiation of

4 2.55
treatment

Intolerance to treatment any adverse event possibly

is best defined as: related to treatment as assessed
by treating physician leading to 8 0.29
potential discontinuation of the
drug

severe steroid related side 8 0.29

effects (acne, hypertension,
psychosis, diabetes,
osteoporotic fractures), side
effects of immunosuppression
leading to discontinuation
(pancreatitis, cytopenia,
hepatitis, gastrointestinal
symptoms, allergic reactions)

inability to reach recommended

standard dose of treatment due 7 0.37
to adverse events
Supplementary Table 2b: all survey questions and results from the second round

Item options Median Disagreement

rating index

Non-response in AIH is no improvement of serum

7 0.52
best defined as: transaminases

no improvement of serum
transaminases and serum 8 0.16
IgG

no improvement of serum
transaminases, serum
IgG and persistent 8 0.29
histological activity (HAI
≥4/18 or equivalent)

no improvement of serum
transaminases, bilirubin 5 0.85
and INR

Non-response in AIH 4 weeks after initiation of

5 0.97
should be determined treatment
no later than:
8 weeks after initiation of
5 0.88
treatment

3 months after initiation of

6 0.63
treatment

6 months after initiation of

6 1.61
treatment

12 months after initiation

3 0.65
of treatment

Insufficient response to 1st line treatment

The following statements will cover the definition of

insufficient response to 1st line AIH treatment.

1st line therapy includes:

Steroid monotherapy (predniso(lo)ne or budesonide)

Or
Steroids (predniso(lo)ne or budesonide) +
azathioprine

Insufficient response to <50% reduction of

4 0.52
1st line treatment is best transaminases
defined as:
persistence of elevated
serum transaminases > 2 7 0.52
x ULN

lack of biochemical
8 0.26
remission

Hepatitis Activity Index

7 0.52
>3/18 on liver histology

ALT and AST >2 x ULN of

normal and IgG > upper 7 0.65
limit of normal

Insufficient response to agree / disagree on 9

1st line treatment may point scale
only be diagnosed if
standard therapy had
been optimized and
adherence proven:

- for azathioprine:
demonstration of 8 0.13
therapeutic 6-TGN
levels

- for steroids: up to 10
mg maintenance
therapy after start with
at least 0.5 mg/kg/day
prednisone/prednisolon
e and slow tapering

Insufficient response to 1 month after initiation of

2.5 0.37
1st line treatment should treatment
be determined no later
than: 3 months after initiation of
5 0.95
treatment

6 months after initiation of 7 0.16

 treatment

12 months after initiation

7 1.09
of treatment

Insufficient response to 2nd line treatment

The following statements will cover the definition of

insufficient response to 2nd line AIH treatment.

2nd line therapy includes:

- 6-mercaptopurine

- mycophenolate mofetil (MMF)

- increased dosage azathioprine (>2 mg/kg)

- low dose azathioprine + allopurinol

- 6-tioguanine

Insufficient response to <50% reduction of

5 0.97
2nd line treatment is best transaminases
defined as
persistence of elevated
serum transaminases > 2 7 0.35
x ULN

lack of biochemical
8 0.16
remission

Hepatitis Activity Index

7 0.22
>3/18 on liver histology

transaminases >2 x ULN

of normal and IgG > 7 0.37
upper limit of normal

Insufficient response to agree / disagree op 9 8 0.13

2nd line treatment may point scale
only be diagnosed if
standard therapy has
been optimized and
adherence proven:

- for 6-MP:
demonstration of
therapeutic 6-TGN
 levels

- for MMF: at least 1

g/day, preferably 2
g/day

Insufficient response to 1 month after initiation of

2.5 0.37
2nd line treatment should treatment
be determined no later
than 3 months after initiation of
5.5 0.52
treatment

6 months after initiation of

8 0.16
treatment

12 months after initiation

6 0.63
of treatment

Supplementary Table 3: Calculation of the disagreement index, adapted from

Lantinga et al.

Variable Formula
IPR Upper limit IPR (67th percentile) – lower limit IPR (33rd
percentile)
IPRCP (lower limit IPR + upper limit IPR) / 2
Asymmetry index Distance between IPRCP and 5
IPRAS 2.35 + (1.5 * asymmetry index)
Disagreement index IPR / IPRA
Abbreviations: IPR, interpercentile range; IPRCP, the central point of IPR; IPRAS,
interpercentile range adjusted for symmetry.

Supplementary Table 4: Pubmed search strategy

1. ((("Hepatitis, Autoimmune"[Mesh]) OR (hepatitis[tiab] AND autoimmune[tiab])))

2. Clinical pathway[mh] OR Clinical protocol[mh] OR Consensus[mh] OR

Consensus development conferences as topic[mh] OR Critical pathways[mh] OR
Guidelines as topic [Mesh:NoExp] OR Practice guidelines as topic[mh] OR Health
planning guidelines[mh] OR guideline[pt] OR practice guideline[pt] OR consensus
development conference[pt] OR consensus development conference, NIH[pt] OR
position statement*[tiab] OR policy statement*[tiab] OR practice parameter*[tiab]
OR best practice*[tiab] OR standards[ti] OR guideline[ti] OR guidelines[ti] OR
((practice[tiab] OR treatment*[tiab]) AND guideline*[tiab]) OR CPG[tiab] OR
CPGs[tiab] OR consensus*[tiab] OR ((critical[tiab] OR clinical[tiab] OR
practice[tiab]) AND (path[tiab] OR paths[tiab] OR pathway[tiab] OR pathways[tiab]
OR protocol*[tiab])) OR recommendat*[ti] OR (care[tiab] AND (standard[tiab] OR
path[tiab] OR paths[tiab] OR pathway[tiab] OR pathways[tiab] OR map[tiab] OR
 maps[tiab] OR plan[tiab] OR plans[tiab])) OR (algorithm*[tiab] AND (screening[tiab]
OR examination[tiab] OR test[tiab] OR tested[tiab] OR testing[tiab] OR
assessment*[tiab] OR diagnosis[tiab] OR diagnoses[tiab] OR diagnosed[tiab] OR
diagnosing[tiab])) OR (algorithm*[tiab] AND (pharmacotherap*[tiab] OR
chemotherap*[tiab] OR chemotreatment*[tiab] OR therap*[tiab] OR treatment*[tiab]
OR intervention*[tiab]))

3. #1 And #2

Supplementary Table 5a: Baseline characteristics. Outcomes in study cohort:

patient with treatment response (≥50% decrease of serum transaminases within 4
weeks after initiation of treatment) vs. patient without a treatment response (<50%
decrease of serum transaminases within 4 weeks after initiation of treatment).
Primary outcome was liver-related mortality or liver transplantation. AIH, autoimmune
hepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LTx, liver
transplantation.

Non-response Response p-value

N=42 N=206

Female sex, n (%) 32 (76.2%) 165 (80.1%) 0.568

Age at diagnosis, 58.90 (12.37) 50.52 (17.97) 0.007

year (SD)

Probable AIH 19 (45.2%) 74 (35.9%) 0.256

diagnosis, n (%)

Definite AIH 23 (54.8%) 132 (64.1%) 0.256

diagnosis, n (%)

ALT, median (IQR) 101 (100) 479 (717) <0.001

AST, median (IQR) 83 (120) 378 (737) <0.001

Cirrhosis, n (%) 19 (46.3%) 36 (19.4%) <0.001

Ltx or liver-related 9 (21.4%) 5 (2.4%) <0.001

death, n (%)

Ltx or all-cause 14 (33.3%) 21 (10.2%) 0.004

mortality, n (%)

Ltx, n (%) 4 (9.5%) 3 (1.5%) 0.009

 Liver-related 6 (14.3%) 3 (1.5%) 0.002
death, n (%)

Supplementary Table 5b: Baseline characteristics. Outcomes in study cohort:

patients with CBR (normalization of serum transaminases and IgG below the ULN,
within 6 months after initiation of treatment) vs. patients without CBR (no
normalization of serum transaminases and IgG below the ULN, within 6 months after
initiation of treatment). Primary outcome was liver-related mortality or liver
transplantation. AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AST,
aspartate aminotransferase; CBR, complete biochemical response; LTx, liver
transplantation.

No CB CBR p-value
N=159 N=134

Female sex, n (%) 117 (73.6%) 103 (76.9%) 0.518

Age at diagnosis, 53.00 (16.44) 52.16 (18.37) 0.399

year (SD)

Probable AIH 51 (32.1%) 55 (41.0%) 0.111

diagnosis, n (%)

Definite AIH 108 (67.9%) 79 (59.0%) 0.111

diagnosis, n (%)

ALT, median (IQR) 319.0 (658) 402.0 (677) 0.678

AST, median (IQR) 263.0 (568) 294.0 (891) 0.313

Cirrhosis, n (%) 43 (29.5%) 22 (18.8%) 0.047

Ltx or liver-related 12 (7.5%) 0 (0.0%) 0.003

death, n (%)

Ltx or all-cause 27 (17.0%) 6 (4.5%) 0.006

mortality, n (%)

Ltx, n (%) 6 (3.8%) 0 (0%) 0.031

Liver-related 7 (4.5%) 0 (0%) 0.026

death, n (%)