AZATHIOPRINE / 6 MERCAPTOPURINE
The purine analogues azathioprine and mercaptopurine are effective in inducing and
maintaining remission in patients with ulcerative colitis and Crohn’s disease.
Azathioprine is a prodrug which is converted to mercaptopurine and then metabolised to
the active metabolite 6-thioguanine. Thiopurine Methyl Transferase (TPMT) converts
mercaptopurine to 6-methyl-mercaptopurine. When TPMT levels are low, higher levels
of 6-thioguanine are produced and this is associated with a greater risk of
myelosuppression.
The onset of action of these drugs is very variable and in many patients, the beneficial
effects may not be seen for 3 – 4 months, and in some cases even longer.
Dosage
Azathioprine : A typical dose regimen may be 1mg/kg/day orally, increasing by slow
titration to a target dose of 2 – 2.5 mg/kg/day. This approach may minimise the risk of
direct and indirect toxicity (see below).
Some centres have access to the measurement of Thiopurine Methyl Transferase
genotyping or enzyme levels. About 1 in 300 of the population have no TPMT and the
drug should be avoided in this group. Similarly heterozygotes with intermediate TPMT
levels should receive lower treatment doses (e.g 50% of standard dose regimen).
Unfortunately the measurement of TPMT levels does not replace the need for careful
haematochemical monitoring as only just over ¼ of cases of myelotoxicity will be due to
patients with TPMT mutations. In nearly ¾ of patients who develop neutropenia no
reason will have been identified.
Measurement of TPMT levels should be considered for patients prior to starting
azathioprine if available locally.
Mercaptopurine : A change from azathioprine to Mercaptopurine should lead to a dose
reduction of about 50%. Incremental dose increases (as with azathioprine) up to a
maximum dose of 1.5 mg/kg orally. As with azathioprine, patients identified as being
heterozygotes / intermediate TPMT levels should receive lower treatment doses.
Direct Toxicity :
Pancreatitis; bone marrow suppression; allergic reactions including nausea, swinging
fevers); drug induced hepatitis.
Indirect toxicity : Infections – bacterial and viral (including herpes zoster and simplex,
Epstein Barr virus (EBV); Cytomegalovirus (CMV).
Limited evidence suggests the possibility of a slight increased risk of lymphoma; a slight
but non significant increase in cervical cancer and an increased risk of non-melanoma
skin cancer (similar findings in the immunocompromised transplant population).
Kandiel et al (1) found a relative risk of 4 for the development of lymphoma in patients
taking azathioprine, but were unable to distinguish between whether this was the result of
the medication, the severity of the underlying inflammatory bowel disease or a
combination of the two.
The recent reports of six cases of hepato-splenic lymphoma in young people on combined
thiopurine/infliximab therapy for Crohn’s disease is of concern. The relative contribution
of each drug is not clear.
There are very few case reports of an association between cervical cancer and IBD
patients taking azathioprine, although there is more evidence available for patients with
rheumatoid arthritis or systemic lupus erythematosus. There are occasional reports of
IBD patients on immunosuppressive therapy developing skin tumours (2).
Laboratory monitoring
Close long term follow up of Full blood count (FBC) and LFT’s is required in all
patients taking AZA/MP. The risk of a patient developing a drug induced neutropenia
may not occur for many months after starting treatment and this is not accounted for by
variations in TPMT levels.
British Society of Gastroenterology
Recommendation
Pre-treatment
assessment
FBC, U&E, creatinine, LFT’s.
Consider TPMT genetic testing or enzyme
levels.
Avoid treatment if TPMT homozygous
recessive or low enzyme activity
Immunisation with influenza and pneumovax
recommended whilst on treatment
Monitoring
FBC & LFT’s weekly for 4 weeks or when
associated with dose increase
Once the dose, disease and blood monitoring
is stable reduce to 3 monthly
U&E, Creatinine at 4, 12 & 26 weeks, then
yearly
What to do if :
1. Bone marrow suppression occurs : Mild – (WCC > 2.5) – reduce dose of
azathioprine and repeat FBC regularly to confirm improvement; Moderate –
(WCC 1.5 – 2.5) stop azathioprine for 1 week, then consider restarting at much
lower dosage with weekly FBC monitoring; Severe (WCC < 1.5) – withdraw
treatment. If patient pyrexial admit for intravenous antibiotics and consider use of
granulocyte-colony stimulating factor (G-CSF).
2. Patient develops pancreatitis : discontinue treatment
3. Patient develops abnormal LFT’s – withdrawal of the drug usually leads to a
resolution of the abnormalities and a liver biopsy is rarely required. Consider
other causes of abnormal LFT’s.
4. Pregnancy : there is no evidence that azathioprine is teratogenic so the
treatment can be continued. Generally azathioprine should not be started
during pregnancy.
Recommendations
- Advise patients to use sunscreens and protective covering to reduce sunlight
exposure.
- Immunisation with LIVE vaccines should be avoided. Influenza and pneumovax
can be given.
- Avoid in patients with hepatitis B/C or history of TB.
- AZA / MP are partly metabolised by xanthine oxidase. Care should be taking in
patients taking allopurinol, as the combination of these drugs may lead to
enhanced effects and increased toxicity. Ideally, the combination of allopurinol
and AZA / MP should be avoided. When the combination is necessary, the dose
of AZA / MP should be reduced by 25% or more to avoid drug accumulation and
toxicity.
- The combination of AZA / MP with amino salicylates can occasionally increase
the risk of neutropenia.
The combination of azathioprine and infliximab treatment is superior to azathioprine
alone for inducing and maintaining remission and complete steroid withdrawal in steroid
dependent patients with active Crohn’s disease (3). However, clearly this approach
carries implications with respect to the increased potential for drug-related toxicity.
Clear recommendations as to the duration of therapy cannot be drawn from the available
literature. In practice, most physicians now intend to continue therapy for 3-5 years, and
discuss withdrawing azathioprine at this time with the patient. It should be made clear to
patients that there is a degree of uncertainty with respect to long-term toxicity if treatment
is continued beyond this time frame.
.
1. Kandiel A et al : Increased risk of lymphoma among inflammatory bowel disease
patients treated with azathioprine and mercaptopurine GUT 2005; 54 : 1121 – 5.
2. Austin AS, Spiller RC. Inflammatory bowel disease, azathioprine and skin cancer :
case report and review of the literature. Eur. J. Gastroenterol. Hepatol. 2001; 13 : 193-4.
3. Lemann M. et al. Infliximab and azathioprine for steroid dependent Crohn’s disease
patients - a randomised placebo controlled trial. Gastroenterology 2006; 130 : 1054 –
61.