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Difficult/unanswered questions in IBD
1. Is there a role for 5-ASA therapy in a patient who is on thiopurines?
Argument in favour of continuing 5-ASA:
Arguments against continuing 5-ASA:
So, what do you do? A practical approach:
2. Discuss the role of thiopurine metabolites in a non responding patient?
Monitoring thiopurine metabolites is important because:
The best probability of response to thiopurines was with levels of 6-TG to be greater than 235 pmol/8X108 RBC. However, a certain percentage (41%) of patient’s do achieve a therapeutic response with levels <235.
Checking thiopurine metabolites (6-TG and 6-MMP) in non responders will thus help us to assess our therapeutic options better. So,
3. Discuss the use of Allopurinol in thiopurine non responders?
Allopurinol treatment may be considered in thiopurine non responders due to preferential 6 methyl mercaptopurine (MMP) metabolism. Allopurinol interacts with thiopurine metabolism and can result in dramatic shifts in the metabolism towards 6-TG and away from 6-MMP. This is quite a potent effect and so prescribing must be done very carefully due to risks of marrow suppression and other adverse events. So:
NB: 6-MMP is also implicated in the pathogenesis of thiopurine induced hepatotoxicity. Hence, Allopurinol can also be used in clinical condition of thiopurine induced hepatotoxicity to induce preferential metabolism towards 6-TG (instead of 6-MMP)
4. Questions about concomitant therapy with biologics
What is the rationale for combining biologics with immunomodulators?
Discuss the evidence for combination treatment (biologics plus immunomodulators)?
How do you start combination therapy? Both the biologic and immunomodulators can be started at the same time, but if on steroids, they can be staggered i.e. start biologics and then at a later date start immunomodulators.
When can you withdraw the combination therapy? Which one should it be?
There are no trials to answer this question
What dose is needed just for preventing immunogenicity?
There are no answers from trials. However, it appears that low dose may be effective for this purpose (7.5 mg weekly of oral methotrexate or 50 mg of Azathioprine)
If you need further help to decide on single or combination therapy, please visit http://www.bridgeibd.com/. You can put in your patient characteristics and check the recommendation based on RAND appropriateness method.
5. How would you deal with loss of response to anti-TNF?
It is critical to distinguish between
In situation I, the patient who is relapsing due to some external factors (infection, antibiotics exposure, possibly stress) may be treated for their acute relapse and return to their stable maintenance dosing of their anti-TNF therapy.
In situation II, the patient may be suffering from some pharmacodynamic alteration of therapy, metabolism and clearance. This will need either a pharmacodynamic adjustment (dose increase or interval decrease or both) or a different strategy altogether.
Options in secondary failure:
How do you choose the most appropriate option?
Measuring antibodies to infliximab and infliximab levels help. Afif et al (Afif W et al. Am J Gastroenterol 2010;105(5): 1133-9) showed that patients with measurable antibodies to infliximab were much less likely to respond to dose adjustments to infliximab than they were to a different anti-TNF therapy. Patients with low trough levels of infliximab (less than 12 mcg/nl was used) responded better to an increased dosing strategy with infliximab than switching to another anti-TNF therapy.
In the UK this issue is at present academic because there is no available commercial resource for measuring either trough levels or antibody levels. Such a resource would be valuable.
Infliximab level | Antibodies to Infliximab | Treatment recommendations |
Elevated | Absent | Switch treatment mechanism |
Elevated | Present | Unclear, consider switching to another TNF-inhibitor |
Not elevated | Absent | Adjust does, interval of Infliximab |
Not elevated | Present | Switch to another TNF-inhibitor |
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