# Cochrane Summary on Azathioprine and 6mp



## kss (Jun 23, 2013)

This post is about a recent (May 31, 2013) report by the Cochrane Collaboration which analyzed 13 randomized trials concerning azathioprine and 6pm. It's called Azathioprine or 6-mercaptopurine for the treatment of active Crohn's disease.  

I'll go ahead and include the punch line: "Azathioprine and 6-mercaptopurine were found to be no more effective than placebo for inducing remission in Crohn's disease." Of course you need to read more of it but that's a big deal. I don't know of a physician who's aware of this result.

I took azathioprine for nearly a decade and decided to take myself off years after having had surgery. Nothing happened with my Crohn's but removing the side effects changed my life. I wrote about my experience in a blog post in case anyone wants to read it here's the link.


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## alex_chris (Jun 23, 2013)

Hey there kss,

I briefly looked at the study you linked to. I can't say anything about its methodology or how it derived to its conclusions, but I know the past studies that were conducted with aza and 6-mp and every single one showed a statistically significant difference between placebo and azathioprine when it comes to long term remission for Crohn's patients. Just as an example, this was one of the earlier studies with this conclusion http://www.ncbi.nlm.nih.gov/pubmed/10796557

From personal experience aza has helped me to get to long term remission, but of course not by itself. I have phased it out before which eventually led to a severe flate up which I could get under control with pred and aza again in 2010. 

Don't get me wrong, I am not saying aza is the best or most powerful drug or that we all should take it forever. EDITED

Of course, if you had side effects from aza it is good that you stopped taking it. Hope you feel well and can manage your Crohn's effectively.


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## rollinstone (Jun 23, 2013)

key word being at "inducing" remission, I think this is attributed to their slow acting nature, the fact that they take around 8 weeks to start working isn't as ideal as pred which can get you feeling good within days. the report goes on to say what a wonderful maintenance drug aza and 6mp are though. I can certainly relate about some of the sideeffects, I had nausea for a while when I first started Imuran, now I get occasional headaches but much more tolerable, ideally i'd like to be off it but I don't wanna risk it. its got me in remission so I don't wanna rock the boat. 

are you currently on any meds?

and cheers for sharing this.


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## kss (Jun 23, 2013)

Eh? I wasn't suggesting it was a useless drug. I was pointing out results from what appears to be the biggest meta analysis on azathioprine and 6mp. It's counter to what I've been told by my physicians over the years. And publication bias is a really big problem. I don't know how the Cochrane study controls for this or if they just pick as many publications as they can find. But please keep in mind that you won't be able to find as many negative studies as positive ones. This is an issue of what academics tend to publish and goes far beyond just drug studies. In doing science both positive and negative results are equally important but they don't show up in the literature that way. I remember a TED talk about this.


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## alex_chris (Jun 23, 2013)

Kss, sorry, I didn't want to offend you. You are right, you did not say it was a useless drug.

Thanks for sharing the study.

All the best,
Alex


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## kss (Jun 23, 2013)

Oh no need to apologize I see how I came off by just quoting that tiny piece of a large complicated study. I should've left that quoted part out in my first post.


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## kiny (Jun 23, 2013)

pubmed link

http://www.ncbi.nlm.nih.gov/pubmed/23633304


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## kiny (Jun 23, 2013)

These are very heavy drugs with very heavy potential side effects that are given out like candy. Should read whole study.


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## alex_chris (Jun 23, 2013)

kiny said:


> These are very heavy drugs with very heavy potential side effects that are given out like candy. Should read whole study.


Well, but the conclusion actually is to use biologics together with aza as in this study  http://www.investor.jnj.com/releasedetail.cfm?releaseid=460323

But that's something I believe you said in another thread is problematic in your view.

I doubt either biologics or immunosuppressives are handed out like candy. I personally have bigger problems with the loose use of corticosteroids and antibiotics. 

Anyway, every drug can be dangerous. If people could get to remission or stay in remission witout drugs, I guess they would. Most people can't.


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## kiny (Jun 23, 2013)

alex_chris said:


> Well, but the conclusion actually is to use biologics together with aza as in this study  http://www.investor.jnj.com/releasedetail.cfm?releaseid=460323
> 
> But that's something I believe you said in another thread is problematic in your view.



Right, well not just my view. Combination therapy has just been shown to increase the chance of specific cancers, and since it seems to offer marginal benefit, there's a good argument to be made that you should avoid this whenever possible.

The thing with these 6mp / imuran, studies is that they are often used as a measuring stick for other drugs.

It has been tested against steroids, it has been tested against EN (EN was just as effective as 6mp), etc. 

It's really hard to know how much merit each study has if you start off with the wrong data.


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## alex_chris (Jun 23, 2013)

Hmmmm, the 2010 study I posted above was pretty large in terms of cases analyzed and combination theory turned out to be effective in 57 % of the patients in inducing long term remission, while side effects seemed to not be any different than with just being on biologics. Do you have a link to the study that suggests otherwise?

I am not doubting what you say, just wondering if you could post a link, because I would be interested in reading up on this subject. Thanks.


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## kiny (Jun 23, 2013)

alex_chris said:


> combination theory turned out to be effective in 57 % of the patients in inducing long term remission, while side effects seemed to not be any different than with just being on biologics. Do you have a link to the study that suggests otherwise?


Studies that show that combination therapy is higher risk than monotherapy you mean? There's been a number of studies that showed that, especially in relationship to cancers.

I don't know if anything changed since then, but all cases of those specific lymphoma cancer were all attributed to combination therapy or 6mp, none to TNF-alpha monotherapy.

http://www.la-press.com/azathioprine-and-infliximab-monotherapy-or-combination-therapy-in-the--article-a2706


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## Clash (Jun 23, 2013)

It seems I also read somewhere that the risk is still there for HSTCL whether you are on the combo therapy of biologic/immunosuppressant or that you have been on one then later the other. The study/article was in the Books, Research section of the forum. When I have time I'll read through and see if I can find it again. I may be reading it wrong.


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## kss (Jun 23, 2013)

This link (http://www.investor.jnj.com/released...leaseid=460323) is a press release. It's from the marketing department of Centocor. Sometimes those get spun differently than what the paper actually says. I dunno in this case I'm just sayin'. 

From the looks of it they had a total of 508 patients in one of three groups. Give the complexity of Crohn's I don't think 170 patients is big at all. Achieving remission 57% (combination therapy) vs 44% (Remicade monotherapy) vs 30% (azathioprine only) is only a difference of 22 people and 44 people respectively. Sigh.  

It would be more useful if they reported the cumulative net decrease in the Crohn's Disease Activity Index among the 3 groups.


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## alex_chris (Jun 23, 2013)

Sorry, kss, here is the link to the actual study http://www.nejm.org/doi/full/10.1056/NEJMoa0904492#t=articleTop

Thanks, kiny, I think the conclusion in the 2011 study you linked to is what most docs today and in the past have followed - a staggered approach of treating people based on severity of inflammation, the patient's history and various other factors. You definitely try to use the least invasive approach and work from there. However, in many, many cases people have problems and constant inflammation for years, surgery etc., at that point combination therapy is defiitely warranted despite a potentially (not verified yet) higher risk of serious side effects.

Here is the text from the 2011 study on when combination therapy is warranted  in the conclusion of the study authors:
"Place in Therapy
Compared with monotherapy with either agent alone, the combination of infliximab and azathioprine shows some therapeutic benefits; however, there is at least a small increased risk of opportunistic infection and malignancy. Recommending combination therapy in all patients would potentially expose some patients with less extensive disease to unnecessary risks and increase costs; therefore, it is important to consider factors that predict a more aggressive disease course.

Clinical factors, endoscopic findings, serologic testing, and molecular testing have been examined as predictors of more aggressive disease. Beaugerie, et al identified independent factors associated with a disabling disease course in the 5-year period following diagnosis which included age ,40 years at diagnosis, perianal disease at diagnosis, and steroids required for initial flare-up. The presence of two or more of these risk factors was associated with a 90% chance of developing a disabling disease.46 Small bowel and anoperineal involvement at initial diagnosis have been identified as predictors of early stricturing and/ or penetrating complications.47 Patients who quit smoking for more than a year have reduced need for steroids and immunosuppressive therapy comparable to nonsmokers unlike CD patients who continue to smoke.48 The presence of a severe endoscopic lesion, defined as a large coalescent and deep ulceration covering more than 10% of the mucosal area in at least one colonic segment, is a strong predictor of colectomy within 8 years of the index colonoscopy.49

Although development of IBD is complex and likely multifactorial, concordance of IBD in siblings and twins is suggestive of a genetic predisposition to develop IBD. In 2001 the nucleotide-binding and oligomerisation domain 2 (NOD2) gene was identified as the first susceptibility gene for IBD. Since then, several other susceptibility genes including single nucleotide polymorphisms (SNP) have been strongly associated with the development of IBD. Recent work by Weersma in CD patients identified an increased risk of more severe disease course in patients where more susceptibility genetic mutations were present.50 

Likewise, immune factors may influence disease activity and clinical course. Variable immune responses to microbial antigens including Escherichia coli outer-membrane porin C (OmpC), Pseudomonas fluorescens CD-related protein (I2), and Anti-Sacharomyces cerevisiae antibody (ASCA) and autoantigens, perinuclear anti- neutrophil antibody (pANCA), may also explain differences in CD complications and severity. In one study, both the frequency and magnitude of immune responses to anti-OmpC, anti-I1, ASCA, and anti- CBir1 flagellin were significantly associated with more aggressive disease in children with CD. Internal penetrating and/or stricturing disease was highest in patients positive for all four immune responses (OR 11; 95% CI 1.5–80.4).51 A commercial test is now available combining serologic immune factors and genetic markers to provide individual probability of complications after CD diagnosis.

Although prospective, randomized clinical trials are not available to definitively guide treatment, patients presenting with one or more of these risk factors for complicated disease course may be ideal candidates for combination therapy with infliximab and azathioprine. The importance of eliminating modifiable risk factors, such as smoking, cannot be overemphasized regardless of whether monotherapy or combination therapy is considered. Patients should be counseled on the impact of smoking on their CD, and provided with access to smoking cessation support, including medications if appropriate."


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## wildbill_52280 (Jun 23, 2013)

i enjoy the philosophy of science and i have a problem with the concept of statistical significance. Even though it is a part of the scientific process and yields decent results, it does not yield absolute certain results, which is a goal in science, absolute and certain knowledge. This is because they cannot control for every variable. just because your control group did slightly worse, cannot be interpreted with any absolute certainty that the drug has an effect. there are just too many variables like the persons diet, disease severity, stress, that go unobserved, or or simply unobservable. factor in some of these other variables, and then you may start to see what the drugs effects may be.

i know about these issues in science, so i am not surprised, but that doesn't mean these methods are flawed, there only so much we can do to study this stuff. its complicated. you are just as good using a sample size of one which would be considered anecdotal and not to "scientific standards". but that's a bit extreme, the use of a control group or placeabo is a good practice, but still the quest for absolute certainty is a tough one.

there is also the possibility that comparing two groups and relying on statistical significance can hide the positive effects of substances, but making them seem as if they were less effective then they actually were.

there is also the possibility, that i dont understand science at all, but, i think i do. this is my opinion, as i have read quite about it about science.


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## DustyKat (Jun 23, 2013)

I have always looked at Imuran/6mp as drugs of maintenance not drugs to induce remission, that is the realm of the EEN, steroids and the biologics. In that context the findings that..."Azathioprine and 6-mercaptopurine were found to be no more effective than placebo for inducing remission in Crohn's disease."...are not surprising. 

Am I wrong in thinking this? 

Dusty.


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## kss (Jun 23, 2013)

kudos wildbill_52280. My educational background is in physics and I used to do statistical computing on large data sets to help find profitable short term trading strategies in commodities markets. The statistics that goes on in these papers is not good. It's often times a joke. It wouldn't fly in other industries, not at all. And you're absolutely right about it not being science. Trying to isolate a variable in a complex dynamical system using statistical significance is a recipe to fool yourself. You might like the blog post I did after being horrified by a azathioprine withdrawal study. It's very practical. 

In the hierarchy of mathematical models statistical modeling is by far the weakest. I think we're stuck with it because of American legislation back in 1962. Lou Lasagna would be the well-intentioned physician we can blame. Dr. David Healy has some very well written blog posts about it: http://davidhealy.org/marilyns-curse/

You struck a nerve. I could go on and on about this topic.


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## wildbill_52280 (Jun 23, 2013)

kss said:


> kudos wildbill_52280. My educational background is in physics and I used to do statistical computing on large data sets to help find profitable short term trading strategies in commodities markets. The statistics that goes on in these papers is not good. It's often times a joke. It wouldn't fly in other industries, not at all. And you're absolutely right about it not being science. Trying to isolate a variable in a complex dynamical system using statistical significance is a recipe to fool yourself. You might like the blog post I did after being horrified by a azathioprine withdrawal study. It's very practical.
> 
> In the hierarchy of mathematical models statistical modeling is by far the weakest. I think we're stuck with it because of American legislation back in 1962. Lou Lasagna would be the well-intentioned physician we can blame. Dr. David Healy has some very well written blog posts about it: http://davidhealy.org/marilyns-curse/
> 
> You struck a nerve. I could go on and on about this topic.


Cool! thanks for the links. Briefly glanced at them. i hope to have time soon to check them out in depth. This david healy guy is very interesting to me.


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## kiny (Jun 23, 2013)

People need better and safer medication, ans as long as those pattents from Infliximab and Humira aren't expired, that's just not going to happen.

They were supposed to expire in 2014, they got an extension to 2015.


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## IAmTheWalrus (Jun 23, 2013)

kiny said:


> Studies that show that combination therapy is higher risk than monotherapy you mean? There's been a number of studies that showed that, especially in relationship to cancers.
> 
> I don't know if anything changed since then, but all cases of those specific lymphoma cancer were all attributed to combination therapy or 6mp, none to TNF-alpha monotherapy.
> 
> http://www.la-press.com/azathioprine-and-infliximab-monotherapy-or-combination-therapy-in-the--article-a2706


No one wants to be on drugs, period, but when you previously had a non existent life, and such drugs have "gave" you back your previous life so to speak, you take those chances. 



> So why do we care about this with inflammatory bowel disease? Well, there are a few more now but initially there were 9 reported cases of this type of cancer with taking a medication called azathioprine.
> 
> Probably can occur with 6-mercaptopurine alone. And then over the past few years there were 16 cases, and I believe 1 or 2 more now, of patients taking infliximab in addition to azathioprine or 6-mercaptopurine. Typically this affects young patients.
> 
> ...


It's from the link in my sig, which I know you believe is some kind of pharmacy conspiracy, take it how you will, but numbers in my quote and your article seem to match up give or take a few.

This will be my only post in this thread, it will eventually turn into a debate, and well, I'm sick of debating on the internet. 

:lol2:


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## David (Jun 26, 2013)

DustyKat said:


> I have always looked at Imuran/6mp as drugs of maintenance not drugs to induce remission, that is the realm of the EEN, steroids and the biologics. In that context the findings that..."Azathioprine and 6-mercaptopurine were found to be no more effective than placebo for inducing remission in Crohn's disease."...are not surprising.
> 
> Am I wrong in thinking this?


That was my thought as well.  If memory serves, the data for maintenance of Crohn's is better though now I'm wanting Cochrane to review that as their analysis of studies is exponentially superior to mine.  

The hardest thing is the primary endpoint for the majority of studies is simple reduction of X on the CDAI.  While nice, I'm not interested in simple reduction of CDAI.  I'm interested in deep stable remission which, for most, in my opinion requires a shotgun approach to treatment, not just western medication.


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## DustyKat (Jun 26, 2013)

^^^^+1

As a side note...I still maintain that the CDAI is prejudicial to Ileal and above Crohn's so have little faith in its usefulness as a tool to predict disease activity. 

Dusty.


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## my little penguin (Jun 26, 2013)

^^ CDAI is mainly to have a universal "measure" for trials and experiments.
so trial abc can be compared to XYZ.
 IT does not really reflect an actual patient or how treatment course should go.

my kid doesn't fit in the box so I have "issues" with CDAI


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## DustyKat (Jun 26, 2013)

Unfortunately it does feed into treatment plans in some countries mlp.


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## Avery (Jul 5, 2013)

Hello, KSS This is a very eye opening thread concerning some prescription medications. I must mention to everyone here that it is very possible to have some control over Crohns without taking any prescription medications. I have been doing so for over 20 years. 

A person has to be very determined to remain on a strict diet etc. It is very important to abstain from certain foods that cause flareups. I have always been able to continue providing for my family during these past 20 years without the symptoms of Crohns causing me to stop working. I still deal with minor symptoms from time to time. Usually because of me deviating from the plan.

I made the decision early in my treatments to discontinue medications, since their side-effects prevented me from doing my job comfortably and safely. I just could not perform my job and take these medications! There are some different natural approaches to treating Crohns effectively, but you will not hear about them in any medical journals, since they do not apply to the medical community. For myself Aloe Vera has been a very important part of helping to minimize the symptoms of Crohns.


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