Crohn's Disease Forum » Treatment » Methotrexate vs Azathioprine

08-07-2018, 12:38 PM   #1
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Methotrexate vs Azathioprine

Based on the research I've done online, considering a conventional "bottom up" approach to drugs for Crohn's, I think there seem to be four main levels, where the lowest level is tried first, and if that doesn't work, the next level is tried:
  1. Mesalazine
  2. Corticosteroids (Budesonide, Hydroxycortisone, Prednisone)
  3. Azathioprine, 6-MP, Methotrexate
  4. Anti-TNF agents

I think it is clear that in level two, budesonide has the fewest side effects, followed by hydroxycortisone and then prednisone.

As for level 3, this is more unclear to me and I haven't come across much data comparing azathioprine to methotrexate in terms of:
  • Which one has the highest cancer risk (lymphoma)
  • Which one is worse for other side effects (sickness, liver toxicity, other)
  • Which one is most effective at inducing remission

Do we know of any reliable studies concerning this? Can anyone here report on their experience if you have tried both?
08-07-2018, 02:04 PM   #2
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Both methotrexate and azathioprine increase your chances of lymphoma, however I am not sure, but I think azathioprine increases your risks slightly more. Those risks though are still extremely small for both medications.

As for side effects, that all depends on the person. Some people will experience more side effects then others.

As for inducing remission, people will typically be on prednisone to help bring down a flare and switch to a maintenance medication to help keep you in remission.

I have tried 6mp and it has not worked for me. I did experience some side effects at first, but after about two months, the side effects got better. I will be starting remicade soon and hope that it will do something for me.
08-07-2018, 05:44 PM   #3
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I would add antibiotics to level 1, Cipro and Flagyl.
I have been on azathioprine alone and with Remicade, and methotrexate with Stelara. Azathioprine was definitely worse, I had leukopenia the whole time I was on it, and got sick continuously. Both made me sun sensitive, but I've not had any other problems with methotrexate, other than increased appetite, which I don't need right now.
08-09-2018, 09:46 AM   #4
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As for inducing remission, people will typically be on prednisone to help bring down a flare and switch to a maintenance medication to help keep you in remission.
So if these two drugs are used for maintaining, rather than inducing remission, is there any solid evidence that tells us how these two drugs compare in effectiveness for maintaining remission?

tuff said:
I would add antibiotics to level 1, Cipro and Flagyl.
That is interesting, my consultant said that he would only consider antibiotics "As a last resort" due to concerns about a long term detrimental effect on gut flora.
08-09-2018, 02:07 PM   #5
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Karl, this is from Medscape. I think it answers some of your questions. The whole article is on Medscape - you have to register to view it but it is free.

I can tell you from a pediatric IBD perspective, pediatric GIs have pretty much stopped using Azathioprine or 6MP - except when absolutely necessary (if a child doesn't tolerate MTX for example).

We were told Azathioprine put you at risk for non-melanoma skin cancer and it puts adolescents/young adults at risk for a rare type of cancer (hepatosplenic T cell lymphoma, which has almost always been fatal). That is so rare there aren't even statistics on it, I believe. And it is more common in males.

It also increases the risk for regular Lymphoma.

As a parent, I feel much more comfortable with MTX. My younger daughter was on Imuran for a while and it is the only medication (she has tried every biologic pretty much) that has caused increased infections, including a staph infection.

That is just what I have heard as a parent. I know in the UK, they still use Azathioprine a lot. In the US, biologics are being used a lot more, even as a first-line treatment.

Induction of remission

The second category focuses on the induction of remission [through treatment].
First, [the evidence for] 5-aminosalicylates (5-ASAs) in mild to moderate disease is very weak. No data show 5-ASAs, and mesalamine in particular, to be effective at the induction of remission.
The same has been shown for the use of antibiotics; by themselves, there really is no role.
There is no role for immunosuppressants. No comparative [evidence] shows that 6-mercaptopurine or azathioprine is better than placebo in the short to medium time range. Although we recognize that these drugs would be helpful in steroid-sparing and weaning [patients] off steroids for the induction of remission, there is no significant benefit.
Corticosteroids may be helpful in symptom derailment, but they are not predictable in the resolution of mucosal disease. Even for mild to moderate and moderate to severe disease, they do not seem to have the best evidence as it relates to the induction of disease [remission].
Biologics (including the tumor necrosis factor [TNF]-alpha antagonists of adalimumab; vedolizumab and natalizumab; and ustekinumab) have positive support for the induction of disease remission, which makes sense based on the literature.

[The third category] focuses on biosimilars. We are certainly seeing this more, and challenges from our pharmacy benefits service as to whether we can save money.
The evidence is that biosimilars are effective and noninferior compared with the parent agents. They can be used for induction and maintenance [therapy in] naive patients. There is still a concern about the cross-immunologic upregulation using biosimilars after a parent drug that could not necessarily be evidence-supported. For biosimilars, beware if you start switching [to them] in patients who are well controlled. I think [the use of them for induction and maintenance therapy] seems to be strongly supported based on this current recommendation.
Maintenance of remission

The fourth category focuses on the maintenance of remission once you have attained mucosal [healing].
Again, the 5-ASA products have no role; there is really no value. Steroids are not used for long-term treatment and have variable results in the short-term induction of remission.
Budesonide may be used in patients with ileitis or right-sided colon disease, but the caveat from this recommendation is not to go beyond 4 months. We have seen adrenal insufficiency in some patients. Again, it is not a good drug in the long term, and you should consider steroid-sparing modalities.
Biologics, including natalizumab, vedolizumab, ustekinumab, and adalimumab, have evidence to support their long-term use in the maintenance phase—that is, once initial remission and mucosal healing have been achieved.
The Postoperative Patient

[The fifth category of interest] focuses on the postoperative patient. It is very difficult to make a decision here.
Data support that [high-risk patients should be put back on biologic therapy within 4 weeks of surgery]. Patients at high risk for recurrence include those with previous surgery for Crohn disease, those who smoke (if they are smokers, you should tell them to stop; that is important and a recommendation in and of itself), and those with penetrating disease. Once [patients no longer have] potential infection concerns, restart therapy. It is recommended that patients use combination therapy if there is a concern regarding the development of antibodies. I do not know that it needs to be routine, but the recommendation is that combination therapy would be the preferred approach.
You could make the argument that if a patient is not high-risk and you choose not to restart immunotherapy or a biologic therapy combination, you should go back and do an endoscopic assessment. We would routinely do this within 3-6 months and look for early mucosal relapse in order to then justify therapy at that point based on what we saw.
These are five areas of interest, but there are many other valuable points here. I think this document will be helpful for us, supplying the best evidence and practice recommendations as we move forward in our continued evolution of enhanced care for patients with Crohn disease.
I'm Dr David Johnson. Thanks again for listening.
Mom of M (20)
diagnosed with Crohn's Disease at 16
Juvenile Idiopathic Arthritis at 12
Juvenile Ankylosing Spondylitis at 16

Mom of S (23)
dx with JIA at 14
Ankylosing Spondylitis at 18

Crohn's Disease Forum » Treatment » Methotrexate vs Azathioprine
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