Azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP) were developed over 50 years
ago by Gertrude Elion and George Hitchings and were initially used clinically in the
management of childhood leukemia and organ transplantation.
The first case report of 6-MP use in inflammatory bowel disease (IBD) was from 1962 , and
since then the use of thiopurines has been well established in the management of moderate to
severe IBD.
Thiopurines offer an inexpensive and effective treatment option for maintenance of remission
of IBD in comparison to biological agents which may be 30 times more expensive .
Although 50-60% of IBD patients respond to thiopurines, a significant proportion of patients
will not tolerate them due to various adverse effects . The adverse effects of thiopurines
may be dose related, patient related or idiosyncratic.
The immunosuppressive effects of thiopurines also increase the rates of opportunistic
infections.
Thiopurines are also associated with a higher rate of malignancies, particularly a malignant
Burkitt-like lymphoma, related to Epstein-Barr virus infection . Other adverse effects of
thiopurine relate to allergic phenomenon.
An idiosyncratic adverse effect of thiopurine use is acute pancreatitis (AP).
Acute inflammation of the pancreas defined by INSPPIRE criteria:
requiring 2 of:
1. Abdominal pain compatible with AP
2. Serum amylase and/or lipase ≥ 3 times upper limits of normal
3. Imaging findings of AP
Drug induced AP is the assumed diagnosis when no other cause of AP can be found, the patient
is taking a drug known to be associated with AP, and symptoms resolve after drug
discontinuation. If pancreatitis re-occurs on re-exposure, the drug is definitely considered
the cause.
While drugs are considered a rare cause of AP and most cases are mild and self limited ,
there is an 8 fold higher risk of AP in IBD patients treated with AZA . Thiopurine induced AP
is usually detected within 4 weeks of starting treatment.
However in the case of thiopurine induced AP, there has been no clear understanding of the
mechanism.
Thiopurine induced AP is generally considered an indication to cease thiopurine therapy, due
to the assumed risk of recurrence of AP on reintroduction.
There exists several case reports and anecdotal evidence that reintroducing thiopurines
following an assumed thiopurine associated AP can be well tolerated.
The investigators hypothesize that AZA and/or 6-MP can be safely reintroduced in the
management of IBD patients following thiopurine-induced pancreatitis.
If in the past the patients were treated with AZA, they will now be commenced on 6-MP, and if
in the past they were treated with 6-MP, they will be commenced on AZA.
Phase:
Phase 4
Details
Lead Sponsor:
Shaare Zedek Medical Center
Collaborators:
Christchurch Hospital Sydney Children's Hospitals Network Sydney Children's Network