Download Review article

Aliment Pharmacol Ther 2001; 15: 1699±1708.
Review article: the treatment of in¯ammatory bowel disease
with 6-mercaptopurine or azathioprine
O. H. NIELSEN, B. VAINER & J. RASK-M ADSEN
Department of Gastroenterology C, Herlev Hospital, University of Copenhagen, Denmark
Accepted for publication 17 June 2001
SUMMARY
The thioguanine derivative, azathioprine, is a prodrug of
6-mercaptopurine that is further metabolized by various
enzymes present in the liver and gut. Azathioprine and
6-mercaptopurine have been used in the treatment of
in¯ammatory bowel disease, i.e. ulcerative colitis and
Crohn's disease, for more than 30 years. However,
widespread use of azathioprine or 6-mercaptopurine in
in¯ammatory bowel disease is of more recent origin, the
primary reason being a long-standing debate on the
ef®cacy of these agents in in¯ammatory bowel disease.
Both drugs are slow acting, which is why clinical ef®cacy
cannot be expected until several weeks or even months
of treatment have elapsed. Consequently, azathioprine
and 6-mercaptopurine have no place as monotherapy in
the treatment of acute relapsing in¯ammatory bowel
disease.
Today, azathioprine and 6-mercaptopurine are the most
commonly used immunomodulatory drugs in the
treatment of in¯ammatory bowel disease. Their clinical
INTRODUCTION
In¯ammatory bowel disease, i.e. ulcerative colitis and
Crohn's disease, is characterized by an up-regulated
intestinal immune defence with an apparently uncontrolled in¯ammatory activity. Persons with in¯ammatory bowel disease live with a chronic, essentially
Correspondence to: Dr O. H. Nielsen, Department of Gastroenterology C,
Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730
Herlev, Denmark.
E-mail: [email protected]
Ó 2001 Blackwell Science Ltd
effects are probably identical, although their exact mode
of action is still unknown. The mode of action of
azathioprine is thought to be multifactorial, including
conversion to 6-mercaptopurine (which acts as a purine
antimetabolite), possible blockade of thiol groups by
alkylation, inhibition of several pathways in nucleic acid
biosynthesis (preventing proliferation of cells involved in
the determination and ampli®cation of the immune
response) and damage to DNA through the incorporation
of thiopurine analogues. However, 6-thioguanine
nucleotides may accumulate in toxic doses in
myeloid precursor cells, resulting in life-threatening
myelosuppression. Azathioprine and 6-mercaptopurine
are further known to alter lymphocyte function, reduce
the number of lamina propria plasma cells and affect
natural killer cell function.
The purpose of this comprehensive review is to suggest
guidelines for the application of azathioprine and
6-mercaptopurine in the treatment of in¯ammatory
bowel disease.
incurable condition that frequently requires the use of
potent drugs to control symptoms. Glucocorticoids are
still the most effective remission-inducing medication
but, for patients who fail to respond and for those who
develop side-effects or require long-term glucocorticoid
treatment, immunomodulatory drugs are important
supplements or alternatives. Ultimately, surgery may
be performed. However, Crohn's disease is panenteric in
nature and therefore surgery can never cure this
condition.
Unfortunately, glucocorticoids have common and
serious side-effects that limit patient acceptance and
1699
1700
O. H. NIELSEN et al.
compliance. Some patients may even refuse to take
glucocorticoids and instead live with symptoms of the
disease. Possible bene®ts of various drugs always need
to be balanced against the risks of side-effects and, in
ulcerative colitis (where colectomy offers a `cure'), there
has been greater reluctance to use immunosuppressive
drugs than in Crohn's disease.
It is obvious that, given the unpredictable course of
in¯ammatory bowel disease, valid conclusions concerning the effects of azathioprine (AZA) and 6-mercaptopurine (6MP) can only be drawn from well-designed,
double-blind, controlled trials. In this respect, it is
important to de®ne clearly the types of patients who
have been shown to respond and not to assume
uncritically that established conclusions can be extrapolated to other disease activity states. The aim of this
review is to present a comprehensive analysis of the
available literature that might be helpful to clinicians
treating patients with in¯ammatory bowel disease.
PHARMACODYNAMICS
The absorption of AZA is 16±50% in healthy individuals, and may be even less in patients with in¯ammatory bowel disease due to their faster intestinal transit
time during exacerbations.1 It is a prodrug that is
cleaved rapidly in the liver to 6MP by the enzyme
glutathione-S-transferase, which is then metabolized in
the liver and gut by one of three enzymes: (a) thiopurine-S-methyltransferase (TPMT), which catalyses the
methylation of 6MP to 6-methyl-MP; (b) xanthine
oxidase, which catalyses 6MP to thiourate; and
(c) hypoxanthine-guanine-phosphoribosyltransferase,
which converts 6MP to 6-thioguanine nucleotides.2
It is not possible to point out a single biochemical event
as the cause of the bene®cial effects of these drugs in
in¯ammatory bowel disease, but AZA or 6MP therapy
inhibits the proliferation of T and B lymphocytes, and
thereby diminishes the production of cytotoxic T cells
and plasma cells. After initiation of therapy with AZA or
6MP, 6-thioguanine nucleotides accumulate slowly in
tissues, which probably accounts for the protracted onset
of action. This intracellular accumulation of 6-thioguanine nucleotides is also believed to be responsible for the
cytotoxic effects of these drugs through the inhibition of
purine synthesis, nucleotide interconversions, DNA and
RNA synthesis and chromosomal replication.3±5 Erythrocyte 6-thioguanine nucleotide concentrations, which
are inversely correlated with the rate of metabolism via
the TPMT pathway, correlate with the response in
childhood leukaemia,6, 7 and a similar relationship may
exist in in¯ammatory bowel disease. However, increased
production of 6-thioguanine nucleotides, which is seen
with TPMT de®ciency due to mutations of the TPMT
gene, leads to toxic levels in blood cells, causing
pancytopenia or isolated leucopenia.
A diminished TPMT activity results in the metabolism
of AZA and 6MP via other enzymatic pathways, leading
to high concentrations of 6-thioguanine nucleotides
and thiourate. Whereas no adverse effects seem to be
correlated with thiourate accumulation, accumulation
of 6-thioguanine nucleotides in myeloid precursor cells
represents a risk factor for thiopurine drug-induced
myelosuppression.8 Thus, ®nding the correct concentration of intracellular 6-thioguanine nucleotides is
crucial. Concentrations that are too high lead to
myelosuppression, and concentrations that are too low
lead to a lack of an effect in patients with in¯ammatory
bowel disease.8, 9
It should be noted that the commonly used drug in
in¯ammatory bowel disease treatment, mesalazine,
inhibits TPMT, but it has not been determined whether
this drug interaction reduces the clinical effectiveness of
AZA or 6MP.10, 11
DOSAGE
Given the risk of serious adverse effects and the fact that
TMPT gene analysis is not available in most treatment
centres, AZA should be introduced at a low dose,
e.g. 50 mg daily (0.5±1.5 mg/kg daily), and increased
gradually to doses of 2.5 mg/kg daily within 2 weeks,
with weekly blood monitoring (i.e. haemoglobin, white
blood cell count, thrombocytes, alkaline phosphatase
and alanine aminotransferase) until the maintenance
dose is reached. Monitoring should then be continued
monthly or every second month for the duration of
therapy. The molecular weight of 6MP is 55% of that of
AZA, and 88% of AZA is converted to 6MP. Accordingly, a conversion factor of approximately 50% exists
between AZA and 6MP. Therefore, the equivalent dose
of 6MP is initially 0.25±0.5 mg/kg daily, increasing to
1.0±1.5 mg/kg daily. If the white blood cell count
decreases below 3 ´ 109/L or the platelet count decreases below 120 ´ 109/L, the drug should be discontinued
or the dose reduced until these parameters normalize.
Furthermore, if liver biochemistry (and/or serum amylase) exceeds more than 50% of the upper limit of
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
REVIEW: IMIDAZOLE PURINE ANALOGUES AND IBD
normal, treatment with AZA/6MP should be discontinued. It should be borne in mind that all monitoring
principles have their limitations, as discussed earlier.12
If warranted, AZA may then be reintroduced cautiously.
Monitoring does not always prevent bone marrow
suppression, which can be sudden in onset, even after
a long duration of treatment, and patients should be
educated to pay close attention to unusual symptoms or
signs of infection.
A recent study has suggested that the measurement of
the AZA/6MP metabolite, 6-thioguanine nucleotide, in
erythrocytes might be helpful in determining the
adequacy of the AZA dosage.13 By gradually increasing
the dosages of these agents, many of the dyspeptic sideeffects can be eliminated. Furthermore, allergic sideeffects detected at low doses, including pancreatitis,
hepatitis, fever and rash, usually appear within the ®rst
weeks of treatment with the drug. However, it should be
emphasized that these side-effects are unrelated to the
bone marrow suppressive effect14 and unrelated to the
enzymatic activity of TPMT.
AZA and 6MP are both slow-acting drugs, and thus
their effect can only be expected after 12±17 weeks of
treatment. A recent study, however, has described
effects after approximately 4 weeks, and possibly AZA
works faster than previously believed.15 Given their
slow onset of action, these drugs have no place as
monotherapy in acute relapses of in¯ammatory bowel
disease, although AZA has been reported to be successful as a single-drug treatment in remission induction
and maintenance of remission of Crohn's disease that
has been treated primarily in conjunction with a
diminishing dose regimen of prednisolone over a period
of 12 weeks.16 Severe adverse effects, apart from bone
marrow suppression, are seen only rarely if the AZA
dose does not exceed 2.5 mg/kg daily or the 6MP dose
does not exceed 1.5 mg/kg daily.
Allopurinol blocks the metabolism of 6MP via the
inhibition of xanthine oxidase,17 and precautions
should therefore be taken in allopurinol-treated
patients. In such patients, it is often adequate to use
half doses of AZA or 6MP. Theoretically, mesalazine
also inhibits TPMT activity, but the clinical signi®cance
of this is presumably minimal.18
INDICATIONS
The majority of ulcerative colitis and Crohn's disease
patients who have three or more ¯are-ups per year that
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
1701
require glucocorticoids, and those who experience a
relapse of symptoms on tapering off glucocorticoids,
bene®t from treatment with AZA or 6MP.19 In the
following, indications for AZA or 6MP use in Crohn's
disease and ulcerative colitis will be described separately.
Crohn's disease
A recent Crohn's disease Cochrane-based meta-analysis
of all AZA references in the period 1966±May 1998
showed that AZA had a positive effect on maintaining
remission in Crohn's disease,20 and a survey of all
patients with in¯ammatory bowel disease treated in
Oxford, UK, in the years 1968±99 showed that AZA
was effective in the treatment of active Crohn's
disease.21 In addition to its well-documented `steroidsparing effect',22, 23 which is also found in the Cochrane
review based on all literature in the period 1966±97,24
a recent study has shown that long-term AZA treatment
speci®cally attenuates severe recurrent Crohn's disease
ileitis.25 Furthermore, AZA, unlike glucocorticoids, has
been suggested to have the potential to improve or even
heal ®stulas in Crohn's disease patients.12, 26, 27 However, several studies included in the meta-analysis
reported to address this issue,12 but do not provide
exact numbers as to the effect on ®stula healing, and
therefore only limited conclusions can be drawn.
Regarding antitumour necrosis factor therapy (i.e.
In¯iximab), concomitant use of AZA seems to inhibit
the formation of human antichimeric antibodies. Also,
pre- and co-treatment during antitumour necrosis
factor therapy with AZA or 6MP has been suggested
to be of bene®cial effect, as the risk of developing serum
sickness might be minimized.28 However, due to the
limited data available, this hypothesis needs to be
substantiated in controlled trials.29
The value of 6MP in the treatment of Crohn's disease
was established by a study performed by Present et al.30
Approximately 75% of patients receiving 6MP were able
to discontinue glucocorticoid treatment, as compared
with about 37% of the placebo-treated patients, and
®stulas healed in 31% of patients treated with 6MP, but
in only 6% of placebo-treated patients. The median
period until effect with oral therapy was 3.1 months,
although some patients did not respond until after
6 months.30, 31 In a recent meta-analysis, the response
correlated with the cumulative dose.12 Furthermore, an
open-labelled pilot study in patients with glucocorticoidrefractory active Crohn's disease showed that intraven-
1702
O. H. NIELSEN et al.
ous AZA (1800 mg) given over 36 h reduced the
response time to a few weeks.32 This effect, however,
was not con®rmed in a 16-week placebo-controlled trial
with an initial intravenous loading dose of 40 mg/kg
AZA, in which patients were started simultaneously on
oral AZA. Nevertheless, with this regimen, clinical
improvement occurred earlier than previously reported
(4±8 weeks).15
Finally, AZA and 6MP might be ef®cient in preventing
relapses after surgical intervention in Crohn's disease.
The evidence is, however, scarce, but an uncontrolled
study showed that treatment with AZA for at least
6 months reduced the relapse in the neoterminal ileum
post-operatively in Crohn's disease.25 In another study
in which Crohn's disease patients underwent surgical
intervention, it was shown that treatment with 6MP for
24 months reduced the relapse rate clinically, endoscopically and radiologically, as compared to placebo,
but no difference was revealed between 6MP and
mesalazine.33 Thus, whether AZA and 6MP have any
place in secondary prophylaxis after Crohn's disease
surgery is still essentially unknown, and larger controlled studies are needed.
Ulcerative colitis
From the survey of all patients with in¯ammatory bowel
disease in Oxford, UK, in the period 1968±99, AZA was
shown to be effective in active ulcerative colitis, with
higher remission rates observed in ulcerative colitis
than in Crohn's disease.21 In left-sided ulcerative colitis,
which often fails to respond fully to glucocorticoids or
mesalazine preparations, AZA and 6MP have been
shown to be useful alternatives.34 Despite this, clinicians have always been reluctant to use AZA or 6MP in
ulcerative colitis, presumably because of the existence of
a `cure' involving total colectomy, which eliminates the
diseased and the potentially diseased mucosa, as well as
the long-term risk of carcinoma.
AZA or 6MP treatment
Pharmacologically, no basic difference has been found
between the actions of AZA or 6MP, emphasizing that
they can be administered on equal indications. In two
minor studies, it has been suggested that 6MP might be
introduced in patients with in¯ammatory bowel disease
intolerant of AZA (excluding those with hypersensitivity
reactions), where continued immunosuppressive ther-
apy is warranted. In more than half of the patients, 6MP
may be tolerated, but the underlying mechanisms have
not yet been clari®ed.35, 36 AZA and 6MP are licensed
for the treatment of in¯ammatory bowel disease in only
a few countries, but they enjoy widespread licensing for
the suppression of rejection in organ transplant recipients. In addition, they are used widely to treat a number
of autoimmune disorders, usually when glucocorticoid
therapy alone has not provided adequate control, but
often also as the drug of ®rst choice.
DURATION OF TREATMENT AND TAPERING
No study has been conducted to show the necessary or
optimal period of AZA or 6MP treatment in quiescent
disease,37 but a retrospective survey of long-term
treatment showed that two-thirds of Crohn's disease
patients remained in remission after 5 years.12 In this
study, it was suggested that relapse was more likely in
females and younger patients, whereas the disease site
did not in¯uence the relapse rate. Candy et al.38
reported that AZA offers therapeutic advantage over
placebo in the maintenance of remission in Crohn's
disease over a period of only 15 months. Sixty-three
patients were randomized to receive either 2.5 mg/kg
AZA or placebo, in addition to tapering of an initial dose
of prednisolone (1 mg/kg), over a period of 3 months.
After this period, there was no signi®cant difference in
remission rates (76% with AZA vs. 66% with placebo)
but, after 15 months of treatment, 42% of those
receiving AZA and only 7% of those receiving placebo
were in remission (which is highly signi®cant).
In another study, the relapse rates of 157 patients in
remission who continued AZA or 6MP for more than
6 months after withdrawal of glucocorticoids were
compared with those of 42 patients who stopped
therapy for reasons other than relapse.27 Relapse rates
at 1 and 5 years were 11% and 32%, respectively, in
the immunosuppressed group vs. 38% and 75%,
respectively, in the group that had discontinued immunosuppressives. It is suggested, therefore, that withdrawal of AZA therapy may be considered in both
ulcerative colitis and Crohn's disease patients who have
been in remission for 5 years or more. However, due to
the small number of patients followed for the longer
time period, the data must be interpreted with caution.
Whether a slow dosage reduction every 6±12 months is
an alternative to stopping treatment abruptly has not
yet been tested in clinical trials. From the Oxford survey
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
REVIEW: IMIDAZOLE PURINE ANALOGUES AND IBD
mentioned earlier,21 it was concluded that the treatment should not be limited to a previously speci®ed
period of time because ef®cacy in in¯ammatory bowel
disease appears to be sustained for at least 5 years.21
As for Crohn's disease, AZA has an important role in
the treatment of chronic active ulcerative colitis, where
it enables the reduction or cessation of glucocorticoids.
Ulcerative colitis patients with frequent relapses, or
those who are unable to achieve complete remission
with prednisolone, particularly those with left-sided or
distal disease, often have considerable collapse of their
lifestyles, but do not wish to have a colectomy
performed with the prospect of ileostomy or an ileal
pouch. Many of these patients achieve prolonged
remission on AZA with improved quality of life.
A clinical trial showed no bene®t of the addition of
AZA in patients with troublesome, chronic, stable
colitis, i.e. patients with chronic, low-grade or corticosteroid-dependent ulcerative colitis, whereas there was
evidence of bene®t in maintaining remission in ulcerative colitis patients with initially moderate and severe
disease activity who achieved remission while taking
AZA.39 Hence, with regard to the maintenance of
remission of ulcerative colitis, for both patients in full
remission and patients with chronic, low-grade or
corticosteroid-dependent disease who have received
AZA for at least 6 months, the 1-year relapse rate was
36% for patients continuing AZA and 59% for those
taking placebo.39
A disadvantage of AZA or 6MP treatment of both
ulcerative colitis and Crohn's disease is the risk of
relapse after stopping these drugs. The chances of
relapse are 37% at 1 year and 66% at 3 years after
discontinuation.21 The percentage of relapse in ulcerative colitis is higher than that reported in Crohn's
disease patients treated with AZA,27 but the ulcerative
colitis patients treated with AZA included troublesome
cases (see above).32
Only uncontrolled reports of the effectiveness of 6MP
in maintaining remission in ulcerative colitis have been
published.40, 41 The use of 6MP in in¯ammatory bowel
disease has been documented, however, in a metaanalysis showing a clinical effect that parallels that of
AZA.12
1703
term effects. These side-effects occur in about 10±15%
of patients with in¯ammatory bowel disease and are
either dose-dependent (e.g. bone marrow depression
(2%) with leucopenia and/or thrombocytopenia) or
dose-independent (e.g. pancreatitis, allergic reactions or
hepatitis) reactions. As described earlier, only myelosuppression is dependent on the TPMT gene.
Bone marrow suppression
Asymptomatic leucopenia was found in 37 of 739
patients (5%), resulting in effective reduction of dosage.42 However, severe leucopenia (< 2 ´ 109/L) was
found in nine patients (1%), ®ve of whom developed
sepsis, pneumonia or upper respiratory infections. Two
of these patients died. Myelotoxicity occurred at any
time from 2 weeks to 11 years of therapy and either
occurred suddenly or progressed over several months.42
Short-term effects
Side-effects detected at low doses, such as pancreatitis
(3.3%), allergic reactions including rash (2.0%), druginduced idiosyncratic hepatitis with hepatocyte necrosis, cholestasis or insidious onset of liver dysfunction
(0.3%) and infections (7.4%), usually occur within the
®rst weeks of treatment.43 Pancreatitis generally recurs
on retreatment, which excludes the use of either AZA or
6MP. In such cases, the pancreatitis resolves upon drug
withdrawal.44 Laboratory monitoring for pancreatitis
does not appear to be warranted unless symptoms
occur. Arthralgia may be related to AZA, and diarrhoea
is a rare side-effect that is easily confused with a ¯are-up
of the underlying in¯ammatory bowel disease. Hypersensitivity reactions occasionally can be severe, with
rash, fever, hypotension and a decrease in liver
function.
Between 5 and 10% of patients stop treatment on their
own initiative because of side-effects, most often during
the ®rst month. Nausea, vomiting and malaise are the
most commonly encountered problems, especially if the
dose is increased too rapidly. Taking the drug with
meals may minimize nausea.
Long-term effects
ADVERSE EFFECTS
Side-effects from AZA and 6MP can be divided into three
areas: bone marrow suppression and short- and longÓ 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
Infections are a theoretical risk of long-term treatment
as a result of the general immunosuppression, including
viral infections such as cytomegalovirus, herpes zoster
1704
O. H. NIELSEN et al.
and hepatitis A and B, as well as bacterial infections
such as liver abscess, pneumonia and septic phlebitis.45, 46 However, such infections have also been
reported in patients with in¯ammatory bowel disease
who do not receive immunosuppressives, and the risk
does not appear to be greater than that in patients
receiving high-dose prednisolone.47
In this context, it is important to emphasize the risk of
potentially lethal opportunistic infections with the use of
glucocorticoids, which is at least as high as and perhaps
higher than that for AZA or 6MP.48 One should bear in
mind that, in contrast to life-threatening infections with
glucocorticoids, a potentially life-threatening leucopenic
episode with AZA or 6MP can be treated successfully
with granulocyte colony-stimulating factor.49 Disregarding these adverse effects, the purine analogues are
safe drugs in experienced hands.
MONITORING
The long-term safety of AZA and 6MP is acceptable,
provided that white blood cell counts and liver enzymes
are measured at regular intervals to prevent the full
development of the serious adverse effects of bone
marrow suppression and liver cell damage.42 As
patients with high TPMT activity presumably have a
poor clinical response to AZA because of the fast
metabolization, it has been claimed that optimal ef®cacy
is seen in the presence of mild neutropenia.50, 51 In
contrast, recent data suggest that leucopenia is not a
marker of ef®cacy.52
Genetic polymorphism controls the TPMT activity and
thus the therapeutic effect and toxicity of AZA. In the
Caucasian population, 89% have high TPMT activity
(two wild-type alleles), 11% have intermediate activity
(one wild-type and one mutant allele) and 0.3% have no
detectable TPMT activity (two mutant alleles),53 which
precisely corresponds with the frequency of severe
myelotoxicity observed during AZA therapy.54
It has been argued that individuals with homozygous
de®ciency of TPMT activity should be identi®ed by
screening prior to treatment and excluded from AZA or
6MP therapy to avoid life-threatening neutropenia.55
However, heterozygous patients also have a potential
risk of developing bone marrow suppression. Thus, a
French study showed that only 27% of Crohn's disease
patients with myelosuppression during AZA treatment
had mutant alleles of the TPMT gene associated with
enzyme de®ciency.56 Therefore, it should be empha-
sized that TPMT measurements cannot yet replace the
need for continued haematological monitoring. As the
determination of TPMT activity is not available routinely at most in¯ammatory bowel disease centres, this
approach should await the results of a North American
controlled trial. Jackson et al.57 have shown that
genotyping is a cost-effective procedure. The TPMT
activity in the liver and kidneys correlates with the
activity of TPMT in erythrocytes, which offers an
alternative monitoring modality. However, this must
await studies clearly correlating erythrocyte 6-thioguanine nucleotide levels with TPMT gene activity and the
risk of adverse effects.
CANCER RISK
Concerns about the potential for AZA or 6MP to
increase the risk for the development of neoplastic
transformations have not been con®rmed in in¯ammatory bowel disease. There is an increased incidence of
lymphoma in transplant recipients receiving AZA or
6MP,58 and cerebral lymphomas occur more frequently
than expected. It has been suggested that the risk of
neoplasia is a particular feature of transplant patients,
but a prospective study of 1349 non-transplant patients
receiving AZA, including 280 patients with in¯ammatory bowel disease, also showed a signi®cant increase in
non-Hodgkin's lymphoma, squamous cell carcinoma
and other tumours (overall risk increased by a factor of
1.6; P < 0.03).58, 59 In contrast, reports from St. Mark's
Hospital (755 patients) and from Oxford (2205 patients)
showed that the overall risk of neoplasia in patients
with in¯ammatory bowel disease was not increased
compared with the general population.60, 61 As the
median duration of treatment in the St. Mark's series61
was approximately 1 year, ®rm conclusions concerning
the risk of lymphoma cannot be drawn. However, the
incidence of colorectal cancer was increased for ulcerative colitis patients and correlated with disease duration,61 but was not greater for those taking AZA than
for other ulcerative colitis patients.60, 61 Thus the
increased risk appears to be due to the underlying
in¯ammatory bowel disease process rather than the
medication.
The development of non-Hodgkin's lymphoma in
patients with in¯ammatory bowel disease on AZA or
6MP has been assessed recently in a study evaluating
both the bene®ts of using these drugs in in¯ammatory
bowel disease and the risk of lymphoma complications.
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
REVIEW: IMIDAZOLE PURINE ANALOGUES AND IBD
It was concluded that the bene®ts far outweigh the
potential risk of neoplasia.62
PREGNANCY AND LACTATION
From a database of over 2800 patients with in¯ammatory bowel disease, 155 patients who had been
pregnant at least once while on AZA or 6MP were
interviewed. The pregnancy outcomes (measured as
full-term births, premature births, spontaneous abortions, congenital abnormalities and neonatal infections)
did not differ from those of women with in¯ammatory
bowel disease not receiving AZA or 6MP.63 Thus, there
is no scienti®c rationale for physicians to advise patients
planning to become pregnant to discontinue AZA or
6MP therapy,64 and AZA and 6MP can be prescribed
safely to fertile women.65
Although both AZA and 6MP cross the placenta,66
no speci®c teratogenic effects have been reported.41, 62
The general risk of teratogenicity is found to be
identical to the level in the background population
(4%).63, 65, 67 Although data on the use of AZA and
6MP speci®cally in pregnant patients with in¯ammatory bowel disease are limited, studies of women
taking AZA or 6MP for kidney transplantation or
rheumatic disorders have not revealed increased
teratogenicity.68 If either drug is essential for disease
control, women should be reassured that continuing
Table 1. Summary of recommendations
Maintenance
dosage
Monitoring
Effect
Drug interaction
Indications
Duration
Pregnancy
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
1705
treatment is compatible with the delivery of a healthy
baby. Additionally, there is no indication for the
termination of pregnancy because of AZA or 6MP
treatment. Cessation of AZA or 6MP treatment during
gestation is likely to be more hazardous, because
relapse may in¯uence the outcome of the pregnancy
negatively, i.e. increase the risk of spontaneous
abortion or premature birth.69 However, breast-feeding is contraindicated in women taking AZA or 6MP
because these agents are excreted in signi®cant
amounts in breast milk.70
Two recent studies have shown that conceiving a child
with a man with in¯ammatory bowel disease undergoing AZA/6MP treatment results in a slightly increased
risk of spontaneous abortion and congenital abnormalities in general.71, 72 Even though one paper has
described decreased male fertility,72 it is the general
opinion that AZA and 6MP do not affect male
fertility.73, 74
CONCLUSIONS
The thioguanine derivatives 6MP and AZA are not
suitable as ®rst-line treatment in in¯ammatory bowel
disease owing to the delay in obtaining clinical ef®cacy.
In the clinical use of these agents, physicians must
maintain a subtle balance between the therapeutic
bene®ts and potential risks or side-effects, and patients
AZA (2.5 mg/kg daily); 6MP (1.5 mg/kg daily)
Initially blood tests every week (haemoglobin, white blood cell
count, platelets, alanine aminotransferase, amylase if abdominal
pain occurs); thereafter monthly or every second month for the
duration of therapy
Ef®cacy of AZA or 6MP may be expected after 3 months of treatment
In allopurinol-treated patients, half dosage of AZA or 6MP should
be applied
AZA or 6MP may be administered on equal indications in both
Crohn's disease and ulcerative colitis with frequent ¯are-ups, and
in those who experience relapse of symptoms on tapering off
glucocorticoid
If tolerated and effective, AZA or 6MP can be continued for
4±5 years
No teratogenic effects of AZA or 6MP have been reported, including
pregnant women with rheumatic disorders or kidney transplantation. However, breast-feeding is contraindicated in women
taking AZA or 6MP. A slightly increased risk of spontaneous
abortion or congenital abnormalities is seen in offspring
of males with in¯ammatory bowel disease on AZA or 6MP
1706
O. H. NIELSEN et al.
must accept the need for regular monitoring after a
thorough education in potential toxicities.
In Crohn's disease, AZA and 6MP are indicated in
chronic active disease that fails to respond to glucocorticoids, or when the prednisolone dosage cannot be
reduced below 10±15 mg, particularly if adverse effects
are problematic. The drugs should be used to maintain
remission, but only in patients with previous extensive
or troublesome chronic active disease. Furthermore,
AZA and 6MP can be administered with advantage to
Crohn's disease patients with ®stulous complications.
In ulcerative colitis, chronic unresponsive glucocorticoid-dependent disease and frequent relapses (more
than three in 2 years) are, in our opinion, indications
for AZA or 6MP treatment. In older patients with longstanding total colitis (10 years or more of pancolonic
ulcerative colitis), concerns about the disease-related
risk of colorectal cancer may outweigh the bene®ts of
drug therapy and therefore result in the need for total
colectomy, whereas AZA or 6MP may have a major
role in younger patients with more recent onset of
disease who wish to avoid surgery. Left-sided disease
more commonly fails to respond fully to glucocorticoids
or mesalazine preparations, and purine analogues are
particularly useful in this subgroup.34 Obviously,
maintenance therapy should be restricted to patients
who have achieved satisfactory remission using these
drugs.
For steroid-dependent patients, AZA and 6MP appear
to be bene®cial in both Crohn's disease and ulcerative
colitis and, for the maintenance of remission, the use of
AZA or 6MP should be considered in both diseases. If
effective, they can be continued for a minimum of
4±5 years, although this period may be much longer. A
summary of the recommendations from this comprehensive review is given in Table 1.
It may be worthwhile to introduce therapeutic drug
monitoring by investigating 6-thioguanine nucleotides
during standard oral AZA therapy so that more insight
into the therapeutic window may be obtained. However,
TMPT genotyping does not appear to satisfactorily
predict the development of myelosuppression. Finally,
it would be useful to design new oral AZA formulations,
which deliver the active metabolites directly to the
in¯amed intestine, in order to reduce the toxicity or
adverse effects and at the same time improve the
therapeutic ratio.
ACKNOWLEDGEMENT
This study was supported by a grant from Else and
Mogens Wedell-Wedellsborg's Foundation.
REFERENCES
1 Tremaine WJ. Refractory IBD: medical management. Neth J
Med 1997; 50: S12±4.
2 Yatscoff RW, Aspeslet LJ. The monitoring of immunosuppressive drugs: a pharmacodynamic approach. Ther Drug
Monit 1998; 20: 459±63.
3 Lennard L. Assay of 6-thioinosinic acid and 6-thioguanine
nucleotides, active metabolites of 6-mercaptopurine, in
human red blood cells. J Chromatogr 1987; 432: 169±78.
4 Sandborn WJ. A review of immune modi®er therapy for
in¯ammatory bowel disease: azathioprine, 6-mercaptopurine,
cyclosporine, and methotrexate. Am J Gastroenterol 1996;
91: 423±33.
5 Lennard L. The clinical pharmacology of 6-mercaptopurine.
Eur J Clin Pharmacol 1992; 43: 329±39.
6 Lennard L, Lilleyman JS, VanLoon J, Weinshilboum RM.
Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 1990; 336:
225±9.
7 Lennard L, Welch JC, Lilleyman JS. Thiopurine drugs in the
treatment of childhood leukaemia: the in¯uence of inherited
thiopurine methyltransferase activity on drug metabolism and
cytotoxicity. Br J Clin Pharmacol 1997; 44: 455±61.
8 Weinshilboum RM, Otterness DM, Szumlanski CL. Methylation
pharmacogenetics:
catechol-O-methyltransferase,
thiopurine methyltransferase, and histamine-N-methyltransferase. Ann Rev Pharmacol 1999; 39: 19±52.
9 Cuffari C, Hunt S, Bayless TM. Enhanced bioavailability of
azathioprine compared to 6-mercaptopurine therapy in
in¯ammatory bowel disease: correlation with treatment ef®cacy. Aliment Pharmacol Ther 2000; 14: 1009±14.
10 Woodson LC, Ames MM, Selassie CD, Hansch C, Weinshilboum RM. Thiopurine methyltransferase: aromatic thiol
substrates and inhibition by benzoic acid derivatives. Mol
Pharmacol 1983; 24: 471±8.
11 Present DH. Interaction of 6-mercaptopurine and azathioprine
with 5-aminosalicylic acid agents. Gastroenterology 2000;
119: 276.
12 Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine
and 6-mercaptopurine in Crohn's disease: a meta-analysis.
Ann Intern Med 1995; 123: 132±42.
13 Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte
6-thioguanine metabolite levels to optimize azathioprine
therapy in patients with in¯ammatory bowel disease. Gut
2001; 48: 642±6.
14 Tanis AA. Azathioprine in in¯ammatory bowel disease, a safe
alternative? Med In¯amm 1998; 7: 141±4.
15 Sandborn WJ, Tremaine WJ, Wolf DC, et al. Lack of effect of
intravenous administration on time to respond to azathioprine
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
REVIEW: IMIDAZOLE PURINE ANALOGUES AND IBD
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
for steroid-treated Crohn's disease. Gastroenterology 1999;
117: 527±35.
Markowitz J, Grancher K, Mandel F, Daum F. 6-mercaptopurine + prednisolone therapy for newly diagnosed pediatric
Crohn's disease: a prospective, multicenter, placebo-controlled
clinical trial. Gastroenterology 1998; 114: A1032(Abstract).
Keuzenkamp-Jansen CW, DeAbreu RA, Bokkerink JP,
Lambooy MA, Trijbels JM. Metabolism of intravenously administered high-dose 6-mercaptopurine with and without allopurinol treatment in patients with non-Hodgkin lymphoma.
J Pediatr Hematol Oncol 1996; 18: 145±50.
Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition
of thiopurine methyltransferase: possible mechanism for
interaction with 6-mercaptopurine and azathioprine. Br J Clin
Pharmacol 1995; 39: 456±9.
Sandborn WJ. Azathioprine: state of the art in in¯ammatory
bowel disease. Scand J Gastroenterol 1998; 33(Suppl. 225):
92±9.
Pearson DC, May GR, Fick G, Sutherland LR. Azathioprine for
maintaining remission of Crohn's disease. Cochrane Database
Syst Rev 2000; 2: CD000067.
Fraser AG, Jewell DP. Relapse rates on and after stopping
azathioprine treatment for in¯ammatory bowel disease. Gastroenterology 2000; 118: A4200(Abstract).
Ewe K, Press AG, Singe CC, et al. Azathioprine combined with
prednisolone or monotherapy with prednisolone in active
Crohn's disease. Gastroenterology 1993; 105: 367±72.
Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R.
A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 1995; 37: 674±8.
Sandborn W, Sutherland L, Pearson D, May G, Modigliani R,
Prantera C. Azathioprine or 6-mercaptopurine for inducing
remission of Crohn's disease. Cochrane Database Syst Rev
2000; 2: CD000545.
D'Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P.
Healing of severe recurrent ileitis with azathioprine therapy in
patients with Crohn's disease. Gastroenterology 1997; 112:
1475±81.
O'Donoghue DP, Dawson AM, Powel-Tuck J, Brown RL,
Lennard-Jones JE. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet
1978; 2: 955±7.
Bouhnik Y, LeÂmann M, Mary JY, et al. Long-term follow-up of
patients with Crohn's disease treated with azathioprine or
6-mercaptopurine. Lancet 1996; 347: 215±9.
Sands BE. Therapy of in¯ammatory bowel disease. Gastroenterology 2000; 118: S68±82.
Bell S, Kamm MA. Antibodies to tumour necrosis factor alpha
as treatment for Crohn's disease. Lancet 2000; 355: 858±60.
Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine: a long-term randomized double-blind study. N Engl J
Med 1980; 302: 981±7.
Rhodes J, Bainton D, Beck P, Campbell H. Controlled trial of
azathioprine in Crohn's disease. Lancet 1971; 2: 1273±6.
Sandborn WJOEC, Zins BJ, Tremaine WJ, Mays DC, Lipsky JJ.
An intravenous loading dose of azathioprine decreases the
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
1707
time to response in patients with Crohn's disease. Gastroenterology 1995; 109: 1808±17.
Korelitz BI, Present DH. Favorable effect of 6-MP on ®stulae of
Crohn's disease. Dig Dis Sci 1985; 30: 58±64.
Ardizzone S, Imbesi V, Bollani S, Bianchi-Porro G, Molteni P.
Azathioprine in steroid-resistant and steroid-dependent
ulcerative colitis. J Clin Gastroenterol 1997; 25: 330±3.
Bowen DG, Warwick SS. Use of 6-mercaptopurine in patients
with in¯ammatory bowel disease previously intolerant of
azathioprine. Dig Dis Sci 2000; 45: 1810±3.
Boulton-Jones JR, Pritchard K, Mahmoud AA. The use of
6-mercaptopurine in patients with in¯ammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol
Ther 2000; 14: 1561±5.
Modigliani R. Immunosuppressors for in¯ammatory bowel
disease: how long is long enough? In¯amm Bowel Dis 2000;
6: 251±7.
Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R.
A controlled double-blind study of azathioprine in the management of Crohn's disease. Gut 1995; 37: 674±8.
Hawthorne AB, Logan RFA, Hawkey CJ, et al. Randomised
controlled trial of azathioprine withdrawal in ulcerative colitis. Br Med J 1992; 305: 20±2.
George J, Present DH, Pou R, Bodian C, Rubin PH. The longterm outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996; 91: 1711±4.
Korelitz BI. A history of immunosuppressive drugs in the
treatment of in¯ammatory bowel disease: origins at the Mount
Sinai Hospital. Mt Sinai J Med 2000; 67: 214±26.
Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone
marrow toxicity caused by azathioprine in in¯ammatory
bowel disease: 27 years of experience. Gut 1993; 34: 1081±5.
Present DH, Meltzer SJ, Krumholtz MP, Wolke A, Korelitz BI.
6-Mercaptopurine in the management of in¯ammatory bowel
disease: short- and long-term toxicity. Ann Intern Med 1989;
111: 641±9.
Stein RB, Hanauer SB. Comparative tolerability of treatments
for IBD. Drug Safety 2000; 23: 429±48.
Lamers CB, Grif®oen G, vanHogezand RA, Veenendaal RA.
Azathioprine: an update on clinical ef®cacy and safety in
in¯ammatory bowel disease. Scand J Gastroenterol 1999;
230(Suppl.): 111±5.
Kirschner BS. Safety of azathioprine and 6-mercaptopurine in
pediatric patients with in¯ammatory bowel disease. Gastroenterology 1998; 115: 813±21.
Matsuda K, Watanabe T, Abo Y, et al. Severe complications of
ulcerative colitis after high-dose prednisolone and azathioprine treatment. J Gastroenterol 1999; 34: 390±4.
Ponticelli C, Tarantino A, Vegeto A. Renal transplantation,
past, present, future. J Nephrol 1999; 12(Suppl. 2): S105±10.
Gerhartz HH, Stern AC, Wolf-Hornung B, et al. Intervention
treatment of established neutropenia with human recombinant granulocyte-macrophage colony-stimulating factor in
patients undergoing cancer chemotherapy. Leukemia Res
1993; 17: 175±85.
Snow JL, Gibson LE. The role of genetic variation in thiopurine
methyltransferase activity and the ef®cacy and/or side effects
1708
51
52
53
54
55
56
57
58
59
60
61
O. H. NIELSEN et al.
of azathioprine therapy in dermatologic patients. Arch Dermatol 1995; 131: 193±7.
Colonna K, Korelitz BI. The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn's disease.
Am J Gastroenterol 1994; 89: 362±6.
Lowry PW, Franklin CL, Weaver AL, et al. Cross-sectional
study of IBD patients taking azathioprine or 6-mercaptopurine: lack of correlation between disease activity and 6-thioguanine nucleotide concentration. Gastroenterology 2000;
118: A788(Abstract).
Vuchetich JP, Weinshilboum RM, Price RA. Segregation
analysis of human red blood cell thiopurine methyltransferase
activity. Genet Epidemiol 1995; 12: 1±11.
Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine
methyltransferase activity. Am J Hum Genet 1980; 32:
651±62.
Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenetics
and metabolite measurement for 6-mercaptopurine therapy in
in¯ammatory bowel disease. Gastroenterology 2000; 118:
705±13.
Colombel J-F, Ferrari N, Debuysere H, et al. Genotypic analysis
of thiopurine-S-methyltransferase in patients with Crohn's
disease and severe myelosuppression during azathioprine
therapy. Gastroenterology 2000; 118: 1025±30.
Jackson AP, Hall AG, McLelland J. Thiopurine methyltransferase levels should be measured before commencing patients
on azathioprine. Br J Dermatol 1997; 136: 132±48.
The Mycophenolate Mofetil Renal Refractory Rejection Study
Group. Mycophenolate mofetil for the treatment of refractory,
acute, cellular renal transplant rejection. Transplantation
1996; 61: 722±9.
Farell RJ, Ang Y, Kileen P, et al. Increased incidence of nonHodgkin's lymphoma in in¯ammatory bowel disease patients
on immunosuppressive therapy but overall risk is low. Gut
2000; 47: 514±9.
Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK,
Lennard-Jones JE. Long-term neoplasia risk after azathioprine
treatment in in¯ammatory bowel disease. Lancet 1994; 343:
1249±2.
Fraser AG, Jewell DP. Long-term risk of malignancy after
treatment of in¯ammatory bowel disease with azathioprine: a
62
63
64
65
66
67
68
69
70
71
72
73
74
30-year study. Gastroenterology 2000; 118: A1471
(Abstract).
Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for
maintenance of remission in Crohn's disease: bene®ts outweigh
the risk of lymphoma. Gastroenterology 2000; 118: 1018±24.
Francella A, Dayan A, Rubin P, Chapman M, Present D.
6-Mercaptopurine is safe therapy for child bearing patients
with in¯ammatory bowel disease: a case-controlled study.
Gastroenterology 1996; 110: A909(Abstract).
Ramsey-Goldman R, Schilling E. Immunosuppressive drug use
during pregnancy. Rheum Dis Clin North Am 1997; 23:
149±67.
Tennembaum R, Marteau P, Elefant E, et al. Pregnancy outcome in in¯ammatory bowel disease. Gastroenterol Clin Biol
1999; 23: 464±9.
Ostensen M, Ramsey-Goldman R. Treatment of in¯ammatory
rheumatic disorders in pregnancy: what are the safest treatment options? Drug Safety 1998; 19: 389±410.
Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJF, Clark
ML. Pregnancy in in¯ammatory bowel disease patients on
azathioprine. Gut 1989; 30: 718.
Davidson JM, Lindheimer MD. Pregnancy in women with
renal allografts. Semin Nephrol 1984; 4: 240.
JaÈrnerot G. Fertility, sterility and pregnancy in chronic
in¯ammatory bowel disease. Scand J Gastroenterol 1982; 17:
1±4.
Committee on Drugs, American Academy of Pediatrics. The
transfer of drugs and other chemicals into human milk.
Pediatrics 1994; 93: 137±50.
Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GW.
Outcome of pregnancies when fathers are treated with
6-mercaptopurine for in¯ammatory bowel disease. Am
J Gastroenterol 2000; 95: 684±8.
Janssen NM, Genta MS. The effects of immunosuppressive and
anti-in¯ammatory medications on fertility, pregnancy, and
lactation. Arch Intern Med 2000; 160: 610±9.
Alstead EM, Ritchie JK, Lennard-Jones JE. Safety of azathioprine in pregnancy in in¯ammatory bowel disease. Gastroenterology 1990; 99: 443±6.
Roubenoff R, Hout J, Petri MX. Effects of anti-in¯ammatory
immunosuppressive drugs on pregnancy and fertility. Semin
Arthr Rheum 1988; 18: 88±110.
Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 1699±1708