DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASE
Dr A.F. Muller DM FRCP
On behalf on the Inflammatory Bowel Disease Committee of the
BRITISH SOCIETY OF GASTROENTEROLOGY
DISEASE MODIFYING DRUGS IN INFLAMMATORY BOWEL DISEASE
This document is designed to provide information for Gastroenterologists, Primary Care Clinicians and patients with IBD regarding the use of disease modifying drugs, their indications, side effects and guidelines for safe monitoring. This document does not cover the use of biological agents whose use is considered elsewhere. It is expected that this information will be made available on the British Society of Gastroenterology and Crohn’s and Colitis Association websites.
1. Azathioprine / 6 Mercaptopurine
4. 5-Amino Salicylates
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.
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 ? of cases of myelotoxicity will be due to patients with TPMT mutations. In nearly ? 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).
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
FBC, U&E, creatinine, LFT’s.
Consider TPMT genetic testing or enzyme Pre-treatment
Avoid treatment if TPMT homozygous
recessive or low enzyme activity
Immunisation with influenza and pneumovax
recommended whilst on treatment
FBC & LFT’s weekly for 4 weeks or when Monitoring
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
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
- Advise patients to use sunscreens and protective covering to reduce sunlight
- 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