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:

  1. 5-ASA has been shown to inhibit TPMT. This will increase 6-thioguanine levels (active metabolite of thiopurines) and hence may increase the therapeutic efficacy of azathioprine/6-MP (not meaningful clinically)
  2. 5-ASA are safe
  3. 5-ASA have possible chemopreventive properties

Arguments against continuing 5-ASA:

  1. No evidence of additive clinical benefit (ref: Andrews et al. Aliment Pharmacol Ther. 2009;29(5):459-69)
  2. Increased risk of leukopenia (due to TPMT inhibition)
  3. More pills may affect adherence
  4. Chemoprevention is of uncertain benefit if patient has already failed primary therapy and if increased inflammation. Further continued 5-ASA treatment does not obviate the need for surveillance colonoscopies, hence it may be argued that continuing additional pills per day is not warranted.

So, what do you do? A practical approach:

  1. If failing 5-ASA, withdraw therapy to confirm that the patient is not intolerant of 5-ASA
  2. If you wish to continue 5-ASA for potential chemoprevention, simplify the regimen (evidence suggest 1.2g/day)

2.    Discuss the role of thiopurine metabolites in a non responding patient?

Monitoring thiopurine metabolites is important because:

  • Standard dosing only 30% effective
  • Safe dose escalation to maximise efficacy
  • Identify non compliance
  • Minimise toxicity
  • Identify preferential 6-MMP metabolism
  • Explain non response
  • Improves patient outcomes

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,

  1. Low (<235) or undetectable levels of 6-TG and 6-MMP suggest under dosing or non compliance
  2. Low (<235) 6-TG and high (>5700) 6-MMP levels suggest 6-MMP shunter. You can use increased dose of thiopurines or consider adding Allopurinol (see below)
  3. Therapeutic (>235-<400) or high 6-TG and high or normal 6-MMP suggests non responder to thiopurines. Will need alternative treatments

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:

  1. Drop Azathioprine to 50 mg or 6-MP to 25mgs a day or approximately to 25% of the prior dose
  2. Start Allopurinol at 100 mgs a day
  3. Weekly blood counts for 4 weeks , then monthly
  4. Checking thiopurine metabolites at 4-8 weeks is informative
  5. Adjust dose as necessary for thiopurine but in small increments

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?

  1. Higher drug levels of biologics
  2. Increased efficacy
  3. Preventing immunogenicity (leading to decreased infusion reactions and reduced loss of efficacy)
  4. Improving drug durability
  5. We don’t understand the pathogenesis of IBD, so biologics and immunomodulators may be acting on different therapeutic targets

Discuss the evidence for combination treatment (biologics plus immunomodulators)?

  1. Patients who are immunomodulators naive, combination treatment is superior to monotherapy for clinical and deep (mucosal healing) remission. SONIC trial (Colombel JF et al. N Engl J Med. 362 (15): p1383-95) showed that combination treatment achieved statistically more mucosal healing and less infusion reactions ( SONIC trial: Primary end point was week 26 steroid free remission: 44.4% with IFX alone and 56.8% with IFX plus Azathioprine i.e. 11% gain)
  2. 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

  3. Patients failing immunomodulators treatment before biologic therapy may not benefit from combination approach. Immunomodulators in these patients can be safely withdrawn after six months without loss of response to the biologic for at least two years (ref: Van Assche G et al. Gastroenterology 2008. 134 (7): 1861-8)

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?

  1. Primary non responder: anti-TNF loading dose ( 2 doses at 0 and 2 weeks) with no response: try a different mechanism (like methotrexate, natalizumab or surgery) and not a different anti- TNF
  2. Primary responder now relapsing (i.e. secondary failure):

It is critical to distinguish between

  1. a patient who has been responding and is stable on therapy but is now suffering from an acute or subacute relapse from
  2. a patient who has demonstrated progressive attenuation of response.

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:

  1. Increased dose
  2. Decreased duration
  3. Switch to a different anti-TNF: Evidence only exists in one direction (infliximab first), assumption is the opposite is true
  4. Different mechanism: methotrexate, natalizumab or surgery

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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