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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?
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.
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.
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.


Staff member
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.
Thanks Maya142, that is interesting.

I brought this question up at my appointment with my consultant yesterday and he said that Azathioprine is preferred over Methotrexate due to something to do with the epstein barr virus. We talked about a lot of other things and I can't quite remember what he said. Does anyone know the full explanation?


Well-known member
San Diego
He was probably referring to reactivation of latent Epstein-Barr virus (EBV) infection by methotrexate - which can result in its own brand of lymphoma.

EBV is a herpes virus that after you are infected will go dormant but not dead, more or less for the rest of your life - unless your immune system gets weakened allowing for viral reactivation. Then like it's herpes cousins HSV, CMV, and Chicken pox, it can come roaring back and causing mischief. Reactivation of various viruses is a common risk factor for nearly all immune suppressants.

I haven't looked in the medical literature for any head to head comparison studies of cancer risk between azathioprine and MTX, but if I had to pick I'd probably go with the MTX. I have an impression it has lower risks. I'll have to look around to see if I can find any studies.
Yes, he said that most people have EBV in their system. Something like 85%, so that is why he recommended Aza instead of Mtx.

If you can find any studies I would be interested. I have not been able to find any.


Staff member
I always thought it was the other way around - It's an issue with Azathioprine if you have had EBV.

We have always been told MTX is safer. They are actually trying not to use Azathioprine for kids with Crohn's, because it is less safe (higher cancer risk - Lymphoma, non-melanoma skin cancer and very, very rarely, hepatosplenic T cell Lymphoma which is almost always fatal). They're using MTX instead.


Well-known member
San Diego
You're not wrong, Maya. EBV + azathioprine is also risky. In fact it is that combo, particularly in young men, that runs the risk of hepatosplenic T cell lymphoma, which is really bad news.

In general I think you are right that MTX is safer than aza with respect to lymphoma. But the risk with MTX is not zero, especially when EBV is involved. That's why I'd like to see a head to head study - to show once and for all that MTX is (or is not) safer.


Staff member
I would definitely like to see a study too! Do you know if MTX has the same skin cancer risks or lymphoma risks? Because we were told that those risks specifically were lower with MTX.

We weren't told anything about EBV - I didn't know it was linked to hepatosplenic T cell lymphoma. That is good to know.

my little penguin

Staff member
Aza and 6-mp both have increased risk of T cell lymphoma in males
Especially when combined with a biologic
This is why Ds GI /rheumo will no longer prescribe young males
Aza/6-mp-especially when they are taking a biologic
We wanted to “try” Aza with Ds humira to see if the Aza would help Ds Sweets Syndrome
Since the humira plus mtx combo was not

I was very surprised when both docs flatoit said absynot
And then explained why
So in the end Ds had to stay on mtx plus humira
And add another drug(second biologic) to treat his sweets Syndrome


Staff member
Just came across this - yikes!! It looks like all immunomodulators put you at risk, while simply using biologics alone does not.

Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk.
Parakkal D1, Sifuentes H, Semer R, Ehrenpreis ED.
Author information
Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. The study of biologic and immunomodulator naive patients in Crohn's disease (SONIC), advocates combining infliximab with an immunomodulator in moderate-to-severe Crohn's disease. Unfortunately, combined immunosuppression increases risk for HSTCL. We herein review all cases of HSTCL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors.

Individual reports from the FDA Adverse Event Reporting System database for lymphomas from the biological agents - infliximab, adalimumab, certolizumab, natalizumab, and etanercept were downloaded and analyzed with Microsoft Access. Full reports for all identified HSTCL cases were obtained from the FDA.

Twenty-five cases of HSTCL were identified. Twenty-two (88%) patients had inflammatory bowel disease and three had rheumatoid arthritis. Four cases (16%) were in women and four patients were above 65 years of age. Twenty-four cases (96%) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate). Two patients received adalimumab alone.

HSTCL is no longer restricted to the previously identified risk group of young male patients, but can also occur in patients with rheumatoid arthritis, females and older adults receiving TNF-α inhibitors and immunomodulators. Improved disease outcomes using combination therapy should be tempered by the risk of developing HSTCL.
T-cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study.
Deepak P1, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y, Ehrenpreis ED.
Author information
The risk of non-Hodgkin's lymphoma (NHL) with tumor necrosis factor alpha (TNF-α) inhibitors is unclear, whether related to concomitant thiopurines usage or due to the underlying inflammatory disease. We sought to review all cases of T-cell NHL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors for all approved indications and examine the risk of T-cell NHL with TNF-α inhibitors in comparison with the use of thiopurines in inflammatory bowel disease (IBD).

The FDA Adverse Event Reporting System (AERS) was queried for all lymphomas following treatment with the following TNF-α inhibitors: infliximab, adalimumab, certolizumab, etanercept, and their trade names. Full reports for T-cell NHL cases were identified using the Freedom of Information Act. In addition, T-cell NHL reported in patients IBD with the use of the thiopurines-azathioprine, 6-mercaptopurine, and their trade names were also collected. A search of MEDLINE was performed for additional T-cell NHL with TNF-α inhibitors or thiopurines, not reported to the FDA but available in published literature. The histological subtypes of T-cell NHL reported with TNF-α inhibitors were compared with reported subtypes in Surveillance Epidemiology and End Results (SEER) -17 registry. Reported risk of T-cell NHL in IBD with TNF-α inhibitors, thiopurines, or concomitant use was calculated using Fisher's exact test using 5-aminosalicylates as control drugs.

A total of 3,130,267 reports were downloaded from the FDA AERS (2003-2010). Ninety-one cases of T-cell NHL with TNF-α inhibitors were identified in the FDA AERS and nine additional cases were identified on MEDLINE search. A total of 38 patients had rheumatoid arthritis, 36 cases had Crohn's disease, 11 had psoriasis, 9 had ulcerative colitis, and 6 had ankylosing spondylitis. Sixty-eight of the cases (68%) involved exposure to both a TNF-α inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-cell lymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-α-inhibitor exposure compared with SEER-17 registry. Nineteen cases of T-cell NHL with thiopurines were identified in the FDA AERS and one additional case on MEDLINE. Reported risk of T-cell NHL was higher with TNF-α inhibitor use in combination with thiopurines (95% confidence interval (CI) 4.98-354.09; P<0.0001) and thiopurines alone (95% CI 8.32-945.38; P<0.0001) but not with TNF-α inhibitor use alone (95% CI 0.13-10.61; P=1.00).

Risk of T-cell NHL is increased with TNF-α inhibitor use in combination with thiopurines but not with TNF-α inhibitors alone
Very interesting information to read.

It would be interesting to know whether biologics and immunomodulators increase the risk of lymphoma by direct action of the chemicals themselves, or instead because they increase the risk of viral infections, and it is the viral infections which increase the lymphoma risk.

My consultant wants to start me on a combination of adalimumab + azathioprine, because I would be regarded as what he described as a "high risk" patient. My recent MRI showed extensive bowel wall thickening and skip lesions.

I asked if he would consider replacing the aza with mtx, but he said that there were more studies and a better evidence base for aza.

I asked a different consultant the same question today and they said that the risks associated with epstein barr are higher with mtx than aza.

I am happy to go along with what they said and have the aza + adalimumab. I need some extensive tests done first to make sure my liver + kidney function is ok and that I don't have TB or any other infection. So I should start in around a month or two.

I am a bit uncomfortable with waiting that long, so am discussing the option of starting Anti-MAP as soon as possible. My consultant is reviewing the literature to see whether there would be any specific concerns of taking aza + adalimumab + Anti-MAP together, although possibly with the Anti-MAP at a lower dose. He said that there would be a higher concern of liver toxicity but my liver stats will be monitored anyway.