PERSPECTIVES IN CLINICAL HEPATOLOGY

Current and Novel Immunosuppressive Therapy for

Autoimmune Hepatitis
Michael A. Heneghan1 and Ian G. McFarlane2

Corticosteroids alone or in conjunction with azathioprine is the treatment of choice in

patients with autoimmune hepatitis (AIH) and results in remission induction in over 80% of
patients. Sustained response to therapy may result in substantial regression of fibrosis even
in advanced cases. The outcome of rapid withdrawal of immunosuppression is disease
relapse in many patients. Consequently, the use of 2 mg/kg/d of azathioprine as a sole agent
to maintain remission has been widely accepted in clinical practice. Persistent severe labo-
ratory abnormalities or histologic abnormalities such as bridging necrosis or multilobular
necrosis are absolute indications for treatment based on controlled clinical trials, but debate
exists as to whether all patients with AIH need treatment. Examination of liver tissue remains
the best method of evaluating both treatment response and need for treatment in patients
who have little biochemical activity. Alternative strategies in patients who have failed to
achieve remission on “standard therapy” of corticosteroids with or without azathioprine or
patients with drug toxicity include the use of cyclosporine, tacrolimus, or mycophenolate
mofetil. Liver transplantation is the treatment of choice in managing decompensated disease.
In this review we examine current management strategies of AIH, and evaluate available data
pertaining to the use of novel immunosuppressive agents in this condition. (HEPATOLOGY
2002;35:7-13.)

Autoimmune hepatitis (AIH) is an uncommon disease, occur-
ring mainly in women, characterized by the morphologic changes
of interface hepatitis on liver biopsy, hypergammaglobulinemia,
elevated serum aminotransferases, and circulating autoantibod-
ies.1,2 Although the pathogenesis is uncertain, AIH is thought to
have a basis in aberrant autoreactivity to hepatocytes in genetically
predisposed individuals. In patients of northern European ethnic-
ity it is associated with inheritance of the extended HLA haplotype
A1-B8-DR3 and with the DR3 and DR4 allotypes.3-5 AIH is no-
tably heterogeneous with respect to its clinical expression and lab-
oratory features and patients may present without obvious clinical
evidence of liver disease or with an acute hepatitis.1,2
Most patients with AIH show a characteristically rapid response
to immunosuppressive therapy. Indeed, AIH was the first chronic
liver disease in which significant improvement in patient survival
was reported following drug treatment.6-9 Standard therapy with
corticosteroids (with or without azathioprine) results in induction
of remission in over 80% of patients. Until recently, patients who
failed to achieve remission with standard therapy often progressed
to cirrhosis, leading to either death or need for liver transplanta-
tion.10 In an attempt to avoid liver transplantation in some pa-
tients, more potent immunosuppression has been used selectively
in the treatment of nonresponders and as primary therapy in un-
controlled pilot studies.11-13 Figure 1 summarizes the sites of action
of current immunosuppressive agents.

Abbreviations: AIH, autoimmune hepatitis; AST, aspartate aminotransferase; ALT,
alanine aminotransferase; 6-MP, 6-mercaptopurine; 6-TGNs, 6-thioguanines;
TPMT, thiopurine methyltransferase; CyA, cyclosporine A; MPA, mycophenolic acid;
MMF, mycophenolate mofetil; UDCA, ursodeoxycholic acid.
From the 1Division of Gastroenterology, Duke University Medical Center, Durham
NC and 2Institute of Liver Studies, King’s College Hospital, Denmark Hill, London,
England.
Received September 20, 2001; accepted November 6, 2001.
M.A.H. is the recipient of an American Association for the Study of Liver Diseases
(AASLD)/Schering Plough advanced liver fellowship award and an American Digestive
Health Foundation (ADHF) TAP Pharmaceuticals Outcomes Research award.
Address reprint requests to: Michael A. Heneghan, M.D., Box 3923 DUMC,
Durham NC 27710. E-mail: heneg003@mc.duke.edu; fax: 919-668-1613.
Copyright © 2002 by the American Association for the Study of Liver Diseases.
0270-9139/02/3501-0004$35.00/0
doi:10.1053/jhep.2002.30991
Natural History of AIH
Mortality rates of up to 80% have been reported in untreated
patients who presented with greater than 5-fold elevations in se-
rum aspartate (AST) or alanine (ALT) aminotransferase activities,
or greater than 2-fold increases in gamma-globulin concentra-
tions.7,8 This is dramatically reversed by treatment. Furthermore,
initial severity or the extent of fibrosis at the start of therapy does
not influence either treatment response or long-term outcomes in
the large majority of carefully managed patients.14-16 Determi-
nants of worse prognosis include an association of the HLA B8
allotype with severe inflammation at presentation and a higher
likelihood of relapse after treatment.10,16 The DR3 allotype, which
is in strong linkage disequilibrium with B8, is also associated with
7
8 HENEGHAN AND MCFARLANE
Fig. 1. This diagram illustrates some of the multiple targets for immuno-
suppressive drugs in AIH. It places some of the novel therapeutic agents in
the context of current “standard therapy.” Many agents target the activation
of T cells and production of cytokines, clonal expansion, or both. Abbrevi-
ations: Ag, antigen; CTLA-4Ig, cytotoxic T-lymphocyte antigen– 4 immuno-
globulin; FK 506, tacrolimus; IL-2, interleukin 2; MHC, major histocompat-
ibility complex; TCR, T-cell receptor; TOR, target of rapamycin.
greater severity of disease, a lower probability of achieving remis-
sion, a higher relapse rate, and a more frequent requirement for
transplantation, as well as a younger age at onset. In contrast,
patients with HLA DR4 are characterized by an older age of disease
onset and a generally more benign outcome.3,16,17 Two main sub-
types of AIH have been characterized based on autoantibody pro-
files. The most prevalent, type 1 comprises patients with detectable
anti-nuclear or anti-smooth muscle antibodies in the serum. Type
2 usually occurs in younger patients, is associated with the presence
of anti-liver kidney microsomal antibodies in serum, and may rep-
resent a subgroup of patients with a less favorable outcome.1,2
When to Treat
Patients who present with an acute onset, with serum AST or
ALT exceeding 10 times the upper normal value, and histologic
evidence of bridging or multilobular necrosis, and/or with severe
hepatic and extrahepatic symptoms, should always be treated, be-
cause mortality may reach 40% within 6 months and 10-year
survival in this group without treatment is only 27%.8,18 In those
who progress rapidly to fulminant (or subacute) liver failure, as-
sessment for liver transplantation should be considered. In general,
however, a greater than 2-fold elevation of aminotransferases in
conjunction with interface hepatitis on liver biopsy is an indication
for treatment. Although some analyses have shown that hepatitis in
the absence of fibrosis is associated with only a low risk of devel-
oping cirrhosis and therefore may result in unaltered life expectan-
cies if left untreated, this is controversial.19 A dilemma that faces
many practitioners is what to do in patients with AIH and normal
aminotransferases. Experience with other liver diseases such as
chronic hepatitis C virus infection suggests that the presence of
even mild inflammatory changes on liver biopsy in the context of
normal biochemistry leads to the development of cirrhosis in 30%
of patients after 13 years,20 and it is noteworthy that 30% to 40%
of AIH patients are already cirrhotic when they first present.21
HEPATOLOGY, January 2002
Furthermore, AIH is characteristically a fluctuating condition that
can apparently spontaneously enter periods of remission only to
flare up (sometimes acutely) later, and serum aminotransferase
activities are not reliable indices of underlying necroinflammation
in this condition.21 For these reasons, we believe that liver biopsy is
useful in determining both the need for, and the response to ther-
apy, particularly in patients with normal biochemistry.
Additionally, as AIH occurs in women of child-bearing age, the
issue of immunosuppressive therapy in pregnancy arises. In the
largest reported series, 31 live births (one twin) resulted from 35
pregnancies in 18 women with AIH, 7 of whom had cirrhosis.22
Two patients presented with AIH de novo during pregnancy. In 22
pregnancies, patients had been receiving azathioprine or pred-
nisolone (alone or in combination) at conception. Fetal loss at or
after 20 weeks’ gestation occurred in only two instances. Flares in
disease activity occurred during 4 pregnancies and within 3
months postpartum in a further 4. Among the 31 children born,
only 2 abnormalities were identified during a median follow-up
period of 10 years. Neither was attributable to immunosuppres-
sion. These findings highlight a number of important points: (1)
AIH can present during pregnancy; (2) standard therapy, particu-
larly azathioprine and moderate doses of corticosteroids (5-15
mg/d of prednisolone), appears to be safe during pregnancy; and
(3) patients who have been in remission on maintenance therapy
quite often suffer relapses either during or after pregnancy and may
require increased immunosuppression.
Corticosteroids and Azathioprine
“Standard Therapy”
The early clinical trials defined what has become “standard
therapy” for AIH.6-9 This involves treatment with prednisone or
prednisolone (40-60 mg/d) alone or a lower steroid dose (20-30
mg/d) in combination with azathioprine (1 mg/kg/d). Both pro-
tocols are equally effective in the management of patients with
severe AIH. Corticosteroids bind to corticosteroid receptor ele-
ments in the promoter regions of numerous steroid responsive
genes, thereby affecting transcription.23 They act rapidly on the
immune system, mainly by interfering with cytokine production
and inhibition of T lymphocyte activation, but they have a rela-
tively short biological half-life, which may explain why intermit-
tent dosing is not effective for controlling AIH.24 Azathioprine, on
the other hand, seems to exert its immunosuppressive effects
mainly through blocking the maturation of lymphocyte precursors
and takes 3 months or more to become fully effective.23
The steroid dose is tapered over a 6-week to 3-month period to
a maintenance dose of 15 mg/d or less. In most cases, aminotrans-
ferases normalize within 6 to 12 weeks. Histologic remission lags 6
to 12 months behind normalization of biochemical markers. Thus,
biopsy-proven remission is the eventual goal in all patients. This is
achieved in 87% of patients within 3 years of treatment, and ap-
proximately 7% of the remainder achieve remission during each
additional year of treatment.
Even in patients with established cirrhosis at the start of ther-
apy, remission can be induced successfully, with 10-year life ex-
pectancies of greater than 90%.14-16 Significant regression of fibro-
sis with steroid therapy has also been reported.25,26 Despite these
promising reports, the issue of how long to treat patients who have
HEPATOLOGY, Vol. 35, No. 1, 2002
Table 1. Therapeutic Algorithm and Future Options in AIH
Standard Therapy
Induction
Prednis(ol)one 40-60 mg/d
Taper to 15 mg/d over 6 weeks
Add azathioprine† when AST decreased to 2-3 times normal range
OR
Prednis(ol)one 20 mg/d and Azathioprine† 1 mg/kg/d
Maintenance of remission
Increase azathioprine to 2 mg/kg/d‡
Steroid withdrawal over 3 months
Cholestatic features
Addition of UDCA 12-15 mg/kg/d in divided doses
Relapse
Prednis(ol)one 40-60 mg/d
Slow taper to 15 mg/d
Treatment failure/fulminant AIH
Orthotopic liver transplantation
*Contraindications to steroids; severe osteoporosis, psychosis, morbid obesity, severe diabetes mellitus.
†Check TPMT genotype if possible prior to initiating high dose azathioprine.
‡Check 6-TG levels for therapeutic levels and 6-MMP to individualize treatment schedules.
achieved complete remission remains problematic. Several con-
trolled trials have investigated medication withdrawal after long
periods in remission on 5 to 15 mg/d of prednisolone and azathio-
prine 1 mg/kg/d.
In one trial of 30 stable patients, only 3 remained in remission
1 year following treatment withdrawal, and these subsequently
relapsed 1.5, 2, and 11 years after stopping treatment.27 In a sep-
arate study, azathioprine was stopped in 27 patients and pred-
nisolone was continued at maintenance doses of 5 to 12.5 mg/d.28
Cumulative probability of relapse within 3 years was 32% in pa-
tients who stopped azathioprine, compared with 6% in 23 patients
who continued on combination therapy. In a further trial, 48
patients were randomized to receive a higher dose of azathioprine
(2 mg/kg/d) after the withdrawal of prednisolone or to continue
with conventional maintenance therapy.29 No patients relapsed
during the 1-year follow-up period on high-dose azathioprine
alone. In a seminal long-term study of 72 patients treated with 2
mg/kg/d of azathioprine alone after withdrawal of prednisolone,
biochemical and histologic remission was sustained in 83% during
a 10-year follow-up.30 Following steroid withdrawal, Cushingoid
facies were lost in all patients and significant weight loss was re-
corded in 50% of the patients. Table 1 summarizes current treat-
ment regimens.
Treatment Failure
Standard therapy for AIH is associated with side effects that lead
to discontinuation of treatment in a proportion of patients. Com-
mon side effects of corticosteroids are usually mild and include
cosmetic changes such as facial rounding, acne, hirsutism, fluid
retention, dorsal hump formation, and obesity and are reversible
with decrease in dosage or withdrawal of the drug.29,30 Severe
adverse side effects that may compel treatment withdrawal include
diabetes mellitus, osteoporosis, cataracts, and psychiatric distur-
bance. Azathioprine has its own toxicity profile including nausea,
vomiting, rashes, pancreatitis, hepatotoxicity, and bone marrow
HENEGHAN AND MCFARLANE 9
Alternative Therapy Future Therapy
Failure of standard therapy or contraindications to steroids* Immunosuppressants
Rapamycin
FTY-720
Cyclosporine to achieve trough levels of 200-250 ng/mL
Immunomodulators
OR CTLA-4 antibody
Tacrolimus to achieve trough levels of 6-10 ng/mL Interleukin 10
Other
OR Oral tolerance
Mycophenolate mofetil 1 g twice daily Gene/stem cell therapy
OR
Cyclophosphamide/methotrexate
OR
Budesonide 6-9 mg/d
Treatment failure
Orthotopic liver transplantation
suppression.29,30 These typically resolve with dosage reduction or
drug withdrawal.
Additionally, in about 10% to 15% of patients the disease ap-
pears to be unresponsive to standard therapy. In our experience,
careful questioning will reveal that some such patients are noncom-
pliant (or only partially compliant) with treatment. In others, fur-
ther investigation may reveal some other underlying condition
such as primary sclerosing cholangitis, primary biliary cirrhosis, or
a variant syndrome such as autoimmune cholangitis. Although
management of variant syndromes is beyond the scope of this
report, a recent review deals comprehensively with this topic.31
Nonetheless, there does appear to be a small core of patients with
definite AIH who are genuinely unresponsive to standard therapy.
Whether these represent a group with a different disease pathogen-
esis or whether treatment failure is caused by genetic differences
between individuals in metabolism of the drugs (see below) is
currently unclear.
Pharmacogenomics of Standard Therapy
Undoubtedly, individual differences in responses to corticoste-
roids are genetically determined but this is a complex area that is
poorly understood. The pharmacogenomics of azathioprine, on
the other hand, are well established. After conversion to 6-mercap-
topurine (6-MP) in the blood, the drug is metabolized via 2 main
pathways: one catalyzed by hypoxanthine-guanine phosphoribosyl
transferase, which converts 6-MP to its active metabolites (the
6-thioguanines, 6-TGNs), and the other involving its conversion
to inactive metabolites through the action of thiopurine methyl-
transferase (TPMT). The genes encoding TPMT are highly poly-
morphic. Up to 6 variant alleles have been identified that encode
enzyme of low (or no) activity, but TPMT can be induced by
azathioprine and it seems that there are also alleles that encode high
activity (or highly inducible) enzyme.32 In most populations, the
frequency of homozygotes with low activity alleles is about 0.3%
and heterozygotes (with intermediate TPMT activities) account
10 HENEGHAN AND MCFARLANE
for up to 11.0%. Individuals with low-intermediate activities pro-
duce larger amounts of 6-TGNs from a given dose of azathioprine
and therefore generally require lower doses for therapeutic effect
(and suffer greater toxicity) than those with high TPMT activi-
ties.32
Patients with AIH should probably be tested for TPMT activity
(phenotype or genotype) prior to initiating azathioprine or 6-MP.
Patients with normal TPMT activity or the wild-type genotype
should receive drug doses (2 mg/kg/d) that have proved efficacious
in controlled trials.30 Those with intermediate TPMT activity or
the heterozygote genotypes should at the outset empirically receive
a lower dose (1 mg/kg/d) and be monitored carefully. Patients with
absent TPMT activity or homozygous for low activity genotypes
should only be treated with great caution at very low doses, and
perhaps not at all. Routine therapeutic drug monitoring of
6-TGNs in patients with AIH has yet to be fully evaluated but may
be considered in selected settings such as in patients receiving
allopurinol or in those who are failing to respond to standard doses
of drug or in patients suspected of medication noncompliance.
Despite this, it is likely that further data pertaining to this technol-
ogy will become more widely available within the coming years.
Other Immunosuppressants
1. Calcineurin Inhibitors
Cyclosporine. Derived from the fungal species Trichoderma
polysporum, cyclosporine A (CyA) exerts its effects by binding to
the immunophilin, cyclophilin.23 This complex inhibits the phos-
phatase activity of calcineurin resulting in decreased transcription
of the Interleukin 2 gene, reduced expression of lymphocyte acti-
vation factors at the cell surface, and impedance of the downstream
organization of inflammatory events by blocking up-regulation of
adhesion molecules and major histocopatibility complex determi-
nants.
CyA has been reported to be effective in small numbers of adult
AIH patients who failed to respond to standard therapy, but re-
lapses occurred when the CyA dose was lowered.33-36 In an open-
label trial, 19 patients (9 treatment-naı̈ve) treated with CyA
showed significant reductions in aminotransferases and histologic
activity index scores over 6 months.13 Serum creatinine did not
change significantly.
In an open-label multicenter study in 32 children with AIH,
CyA was administered alone for 6 months (target trough levels
200-250 ng/mL) followed by low doses of prednisone and azathio-
prine for 1 month, after which CyA was discontinued.11 Two
patients were withdrawn from the study: one for noncompliance
and the other for liver failure unresponsive to CyA. Of the remain-
ing 30 patients, ALT normalized in 25 by 6 months and in all by 1
year. Adverse effects of CyA were mild and disappeared after drug
withdrawal. In another study, 15 children and adolescents with
type 2 AIH were treated with CyA (in 8 as primary therapy because
of risk factors for poor tolerance of steroids and in 5 with relapsing
AIH who refused to resume standard therapy).37 ALT activities
normalized in all within 6 months with minimal side effects. No
relapse occurred in 10 patients after 1 to 6 years. CyA was with-
drawn in 3 patients after 1, 2, and 3 years and replaced by low doses
of prednisone in combination with azathioprine. The two remain-
ing children, who presented with acute liver failure that was unre-
HEPATOLOGY, January 2002
sponsive to standard therapy, showed a dramatic response to CyA
with normalization of clotting parameters.37
Of all alternative agents, the greatest experience to date has been
with CyA. The principal difficulty in advocating widespread use of
the drug as first-line therapy relates to its toxicity profile, particu-
larly with long-term use (increased risk of hypertension, renal in-
sufficiency, hyperlipidemia, hirsutism, infection, and malignancy).
Despite these reservations, the use of CyA as a salvage therapy is a
reasonable alternative to prolonged high-dose corticosteroids.
Tacrolimus. Tacrolimus (FK 506) is a macrolide antibiotic
with an immunosuppressive activity estimated to be 10 to 200
times greater than that of CyA. The mechanism of action is similar
to that of CyA but it binds to a different immunophilin (FK
binding protein). In an open-label preliminary trial in 21 patients,
tacrolimus treatment (at trough drug levels of 0.6-1.0 ng/mL)
resulted in biochemical improvement after 3 months.38 Blood urea
nitrogen (BUN) levels and serum creatinine increased after 1 year
of treatment. In another preliminary study, using lower doses of
tacrolimus in combination with reduced dose prednisolone (20
mg/d), significant improvement in AST, bilirubin, albumin, and
prothrombin time was observed in 6 of 7 patients with severe
new-onset AIH.12 The greatest biochemical responses were noted
in patients who presented acutely without evidence of cirrhosis.
2. Second Generation Corticosteroids
Budesonide. Budesonide is a second generation corticosteroid
with an affinity for the glucocorticoid receptor approximately 15
times that of prednisolone. Taken orally it has a 90% first pass
metabolism in the liver, where the drug may reach pathogenic
lymphocytes at high concentrations prior to elimination, making it
virtually devoid of systemic side effects. Budesonide has been eval-
uated in 2 studies in AIH. In one study of 13 patients (11 of whom
had suffered complications with standard therapy) treated with 6
to 8 mg/d, tapering to 2 to 6 mg/d after 6 to 10 weeks, improve-
ment in ALT and serum IgG without steroid side effects was doc-
umented.39 A second study evaluated budesonide (9 mg/d) in 10
patients who were dependent on continuous treatment to prevent
exacerbation of their disease.40 Three patients entered clinical and
biochemical remission after 5 months, but 7 either deteriorated
during therapy or became drug intolerant.
Deflazacort. Deflazacort is an oxazolinic derivative of pred-
nisolone with fewer effects on bone and glucose metabolism than
the parent molecule. In an open-label trial, 15 patients with AIH in
remission on standard maintenance therapy were converted to de-
flazacort 7.5 mg/d.41 Mild elevations in ALT and IgG were seen in
most patients without apparent sequelae. Remission was sustained
during 2 years of follow-up. The long-term role of second genera-
tion steroids as an alternative to avoid systemic side effects of pred-
nis(ol)one requires further evaluation.
3. Antimetabolites
Mycophenolate Mofetil. Mycophenolic acid (MPA) was orig-
inally isolated from the fungal genus Penicillium. Structural mod-
ification resulted in a more bioavailable oral compound, mycophe-
nolate mofetil (MMF), which is converted to MPA and conjugated
in the liver. MPA is a noncompetitive inhibitor of inosine mono-
phosphate dehydrogenase, which blocks the rate-limiting enzy-
HEPATOLOGY, Vol. 35, No. 1, 2002
matic step in de novo purine synthesis. As lymphocytes tend not to
use this salvage pathway for purine metabolism, MMF has a selec-
tive action on lymphocyte activation, with marked reduction of
both T and B lymphocyte proliferation.
A single study in 7 patients with AIH refractory to standard
therapy has been reported.42 Patients received MMF (2 g/d) in
addition to prednisolone over a median follow-up of 46 months.
Five patients normalized aminotransferases after 3 months. Pred-
nisolone requirement reduced from a median of 20 mg/d to 2
mg/d after 9 months, with a significant improvement in histology.
One patient exhibited bone marrow suppression that required dose
reduction. No other adverse effects were seen. Based on its effects
on both T and B lymphocytes, MMF would seem to be the most
logical second-line agent for treating AIH. There is a pressing need
therefore for a randomized controlled trial comparing its efficacy to
azathioprine in such patients.
Cyclophosphamide. Successful long-term treatment with cy-
clophosphamide has been reported in 3 patients.43 Remission was
induced with 1 to 1.5 mg/kg/d of cyclophosphamide in combina-
tion with a tapering dose of corticosteroids beginning with 1 mg/
kg/d. Histologic remission was maintained with 2.5 to 10 mg/d of
prednisolone together with 50 mg of cyclophosphamide on alter-
nate days. No patient relapsed or suffered severe side effects over a
cumulative observation period of more than 12 years.
Methotrexate. Methotrexate is an antimetbolite with both im-
munosuppressant and antiproliferative effects. There is a single
case report describing a 52-year-old woman who was intolerant of
azathioprine and whose AIH could not be controlled with pred-
nisone alone.44 The patient refused CyA but opted for methotrex-
ate 7.5 mg/wk by mouth. This resulted in normalization of liver
enzymes, improvement in liver histology, and maintenance of re-
mission.
4. Nonimmunosuppressive Therapies
Ursodeoxycholic Acid. Ursodeoxycholic acid (UDCA) has
been shown to have beneficial effects in patients with cholestatic
liver diseases, suggesting that it has immunomodulatory effects,45
and its use in AIH has been examined in 2 studies. In one, signif-
icant biochemical improvement was reported in 8 patients treated
for 2 years with UDCA (600 mg/d).46 Four patients who under-
went liver biopsy after 1 year of treatment showed improvement of
inflammation but not of fibrosis. In a second study, 37 patients
refractory to standard therapy were randomized to UDCA (13-15
mg/kg/d) or placebo for 6 months in addition to their usual corti-
costeroid schedule.47 Although some biochemical improvement
was seen in the UDCA group, this was not statistically significant
and no differences were noted in histologic indices pre- or post-
therapy. These preliminary data suggest that longer term treatment
with UDCA may be required to see significant improvement in
disease indices. However, its role in AIH needs to be defined more
fully.
D-Penicillamine. D-penicillamine is a modified amino acid
with anti-inflammatory and metal chelating properties, which has
been used for many years in the treatment of rheumatic disorders
and Wilson’s disease. Two controlled trials have investigated its use
for sustaining remission in AIH patients who responded to stan-
dard therapy. Both found that, although remission could be sus-
HENEGHAN AND MCFARLANE 11
Table 2. Algorithm for Treatment Withdrawal in Patients With
AIH in Sustained Remission
Maintenance therapy
Prednis(ol)one 5-15 mg/d or azathioprine 2 mg/kg/d
Normal biochemistry for at least 2 years
Liver biopsy shows no activity
Wean prednis(ol)one by 2.5 mg every 3 months
Check aminotransferase and gamma globulin levels monthly
Wean azathioprine by 25 mg every month
Check aminotransferase and gamma globulin levels monthly
Flare in disease activity requires reintroduction of steroids as in Table 1
tained, there were significant side effects (rashes, cytopenia, pro-
teinuria), even at relatively low doses, and concluded that
D-penicillamine may be of use in some patients but does not offer
significant advantages over standard therapy.48,49
Withdrawal of Immunosuppression
As discussed previously, it has been possible to withdraw ste-
roids and replace them with a steroid sparing agent such as azathio-
prine in many patients. Complete withdrawal of all immunosup-
pression is a separate issue and should probably be only attempted
after biochemical and histologic remission has been maintained for
at least 2 years. When attempted, the approach should be slow and
systematic. In a recent uncontrolled study, sustained remission
after drug withdrawal was significantly more likely (67% probabil-
ity) in patients who had received a total duration of therapy of 4
years.16 In contrast, patients who received 2 to 4 years of continu-
ous therapy had a probability of 17%, and patients who received 1
to 2 years of therapy had only a 10% chance of sustained remission
after withdrawal of therapy. For that reason, close attention to
serum aminotransferases on drug withdrawal is necessary and a
flare in disease activity may reflect a need for lifelong low-dose
immunosuppression. Table 2 summarizes our recommendations
for drug withdrawal.
The Future
Without doubt, further advances will result in increased treat-
ment options for patients with AIH. Already, rapamycin, recom-
binant interleukin 10, and antibodies against tumor necrosis factor
are being used in a wide variety of clinical settings. FTY-720, a
novel immunosuppressant that mediates its effects via the induc-
tion of lymphocyte apoptosis and alteration of lymphocyte homing
holds significant promise.50 Other site-specific approaches that will
evolve as pathogenic mechanisms are clarified include the induc-
tion of oral tolerance and blockade of lymphocyte costimulatory
pathways in addition to gene and stem cell therapies.
Finally, given the current array of choices available to clinicians
and patients, several considerations must be taken into account in
the treatment of AIH. First, we have now accumulated 30 years of
experience in the use of standard therapy (either steroid mono-
therapy or in combination with azathioprine), which results in
disease remission in over 80% of patients. Furthermore, despite the
cosmetic and (less frequently) more serious side effects, when dos-
ages are carefully and individually tailored to sustain long-term
remission it is fairly well tolerated by many patients. Secondly, the
12 HENEGHAN AND MCFARLANE
long-term side effects of the novel immunosuppressants have not
been fully evaluated in non-transplant patients. It is therefore likely
that, at least for the immediate future, alternative immunosuppres-
sants should continue to be used selectively. Despite these reserva-
tions, many of these agents offer significant promise and, as greater
understanding of their risks and benefits is acquired, they will be
increasingly used. However, AIH is a rare disease and multicenter
clinical trials will be required to provide sufficient randomized data
to support the use of alternative agents as first-line therapy.
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