6-Mercaptopurine (6-MP) and Azathioprine for the Treatment of Crohn's Disease

[David]

The article, "6-Mercaptopurine and Azathioprine for Treatment of Crohn's Disease" by Burton I. Korelitz is found on pages 655-660 of the book, "Advanced Therapy in Inflammatory Bowel Disease" and is supported by 27 references. For any of you interested in the deeper medical side of Crohn's Disease, this book is fantastic. This thread will contain information I feel is useful in the article and I also open it up for discussion.

- 6-MP was first used to treat Crohn's Disease over 40 years ago.
- The author feels that if a patient has responded well to 5-ASA or steroids, then maybe immunosuppressives aren't needed.
- It can take 3 weeks to 6 months for successful response from 6-MP and Aza.
- In children, pediatric GIs are often recommending 6-MP as the first treatment since early onset Crohn's is often more serious.
- They feel checking CBC and liver function BEFORE and after starting 6-MP and AZA is useful so a trend can be established.
- The author states that the starting dose of 6-MP is usually 50mg and is NOT dependent on weight.
- Feels CBC should be done weekly for the first 3 weeks
- Dosage should be changed if signs of Leukopenia arise - WBC less than 3500, low platelets, or new signs of anemia.
- IV/oral steroids at the same time as 6-MP/AZA will, "elevate the total WBC count, coincidentally providing added safety".
- After 2 weeks of stable WBC then the CBC can be done every other week, then monthly, then longer durations.
- If the patient relapses during this introduction then the dose should be increased and weekly CBC should recommence.
- Those who develop leukopenia (WBC less than 5000) achieve remission faster than those who don't and maintain remission longer. David personal note -- read that study: "The role of leukopenia in the 6-mercaptopurine induced remission of refractory Crohn's disease."
- The author does not suggest increasing dose to induce leukopenia but some is ok as long as it doesn't get worse.
- The author feels that early reactions such as myelosuppression, infections, nausea, vomiting, and fatigue are reversible. He suggests reintroducing in lower doses then increasing it. This usually doesn't work if pancreatitis is present.
- 6-MP may decrease the risk of colon cancer.
- There is a small but statistically significant increased risk of lymphoma on 6-MP and AZA and basal/squamous cell skin cancer.
- Thrombocytopenia is less common than leukopenia and platelet count will often stabilize at a safe level.
- Data suggests continuing the use of AZA or 6-MP rather than stopping it after prolonged remission.

6-MP/AZA and Pregnancy
- A study out of Mt. Sinai suggests these medications are safe to use when pregnant.
- If Crohn's Disease is the more serious problem during pregnancy, then using a drug that is less dangerous makes sense.
- A study out of Lenox Hill Hospital found 23% versus 13% of controls experienced spontaneous abortions and 3% versus 0% experienced ectopic pregnancies.
- The male taking 6-MP/AZA may result in increased risks.
- If IBD has been in remission for months or years the author feels it's ok to stop during pregnancy.
- If the male is taking 6-MP/AZA and in remission then stopping the medicine for 1-3 months before conception might be warranted.
- In the end, the author feels there is no conclusion as of yet.

Managing 6-MP/AZA with Biologics

No response or starting to fail
- Increase dose
- Add biological
- Add 5-ASA
- Surgery

No response or failure with biologic
- Increase dose
- Decrease time between dosages
- Add 6mp or AZA
- Change the biologic
- Steroids
- Surgery

Failure with combined therapy
- Increase dose of 6-MP or AZA
- Decrease time between dose of biologic
- Add 5-ASA
- Stop biologic if having reaction to it
- Stop AZA/6-MP if symptoms are attributable to it
- Surgery

Stopping 6-MP/AZA or biologic after remission
- To be considered only after 1 year of remission
- Reduce dose and increase interval of biologic first
- Potentially stop 6-MP/AZA instead
- Author prefers to stop biologic instead
- Reduce dose of both

 

[David]

Here's the study I made a personal note regarding because I wanted to find and read it. It turns out it's the authors own study.

While it was interesting and I learned some things, this article left my forehead scrunched multiple times for a variety of reasons including:

1. He says 50mg of 6-MP to start for everyone. Yet the majority of GIs use weight based dosing.

2. He makes no mention of TPMT or metabolite monitoring.

3. He mentioned that steroids can be used to concurrently to raise WBC levels for additional safety but then talks about how moderate Leukopenia is beneficial. In addition, if 6-MP dosing is raised while on steroids which are raising the WBC to safe levels, what happens when the steroids are stopped?

 

[DustyKat]

1. I wonder if TPMT testing has also had an influence over dosing David?

When Sarah was diagnosed we did not have the TPMT test available in Australia so she was commenced on 50mg and she has remained at that dose as symptoms did not reappear. When Matt was diagnosed he was commenced on 50mg, the GI felt that because Sarah had no issues he wouldn't either, but when the TPMT result was returned 5 weeks later showing he had the required enzyme he immediately upped him to his weight based dose of 100mg.

3. He mentioned that steroids can be used to concurrently to raise WBC levels for additional safety but then talks about how moderate Leukopenia is beneficial.

Perhaps when he saying to adjust the dose of 6mp, reduce, and add steroids he is looking to have the leucopaenia raised from unsafe levels to below normal but still safe levels, so between 3.5 - 5?

 

[kh216]

Very interesting article, David. 6mp is working very well for me in controlling my Crohn's Disease but I do have a problem with low white blood count. I can't see my GI doctor giving me steroids to raise my WBC because I have been diagnosed with osteoporosis. Also, the whole purpose of 6mp was to lessen my dependence on steroids.