'Odd' remicade question... curious

The way I understand that remicade works is that, in some way (ie blocking TNF, etc.), it turns down the inflammatory response, right? Now, is that ONLY for intestinal inflammation?

I'm asking because Stephen has an old shoulder injury (since Nov. 2011), even after it 'healed', it's continued to bother him sporadically but not very often. He's complained about it a number of times lately and, while I'm not completely certain of this, I'm beginning to wonder if it's been more often since remicade?? It's not actually the shoulder joint, its the muscle/tendon?? that runs from the shoulder to neck.

So, I'm wondering does remicade alleviate/minimize inflammation anywhere in the body?

Also wondering, in normal situations, the inflammatory response is part of the healing process, if remicade is indeed lessening all-over inflammatory response, could this be a factor to the increased occurrances of his shoulder pain?

Then again, perhaps there's absolutely no connection at all :ybatty: and it's just coincidental that it's been bothering him lately???

Aha we are both playing the "Could this be due to" game!!!

Let's see, my understanding is that when you are dealing with an immunosuppressant like MTX,AZA than it is a broad suppressant of the immune system but when dealing with an anti-tnf then you are suppressing tnf and all the actions it has in immune response.

Now, how that would relate to an old shoulder injury I'm not entirely certain, heck I'm not even certain the explanation in the above paragraph is accurate. I guess the answer would be determined by does TNF play a role in the response to a shoulder injury.

I'm going to tag Kiny, he can clear up any damage I've done with my post and probably give more information as well!

They use it for arthritis treatment so cant be just for intestines!

Ive always found injuries to take ages to heal, and if bad enough are never quite right again. This is even before I was put on remicade (2years ago). Bones normally heal quickly but muscles and tendons are notorious for healing slowly

I broke my wrist last year and if I put it through a lot of work I can still feel it aching quite a bit. Ive been told it can take up to 4yrs before it gets its full strength back.

I also twisted my ankle when I was 11 or so, and when I go swimming 15yrs later it still gives me jip.

If it is that bad it would be worth seeing a physio to help it heal quicker and better.

Clash - yes, easy to start the 'hmmmm?'. :lol: when he said it was hurting again, I initially just thought he tweaked somehow but then started thinking I've been thinking that quite a few times lately??? We don't hv a GI apptmt till august but think I'll start my list of questions for next apptmt.

Rygon - yes, I agree muscles/tendons can take a long time. His injury was a 'mild' separation so certainly did pull on a few tendons, etc. He did have physio and has found that a few yoga classes, extra stretching and tiger balm help... And truly cud just be coincidental but as he's just finished his remicade loading doses so as the remicade is a bit new, just made me wonder how systemic the remicade impact is???

Sounds like your boy is just angling for more hot yoga classes with scantily clad women to me:ylol:

Dunno, I don't think they really know what it does exactly.

There's lots of white blood cells in the intestine in people with crohn's disease. Why they're there is a mystery, normally you need an APC, antigen-presenting cell, that presents part of a bacteria to the lymphatic system and you'll get lots of T Cells or B Cells, lymphocytes, to home onto specific tissue to rid it of bacteria. It's possible that that's happening in crohn's disease, but you can't complete the event since there's macrophage deficiencies in people with crohn's disease (nod2, ATG16L1), you never properly kill the bacteria, so you get continuous inflammation. Which bacteria is actually triggering the APC is the holy grail question.

There another pathway why all the white blood cells might get there, and that's through the peyer's patches, they're like mini lymphatics systems, covering the intestine.

Anyway, those white blood cells, macrophages, lymphocytes, etc can all signal each other, they do this by releasing cytokine, one of them is TNF alpha. All those white blood cells have receptors for those cytokine, like a mailbox, infliximab binds to the TNF and makes it so it never arrives in the mailbox of other white blood cells, it stops an inflammatory cascade.

There's something special about infliximab though, it's one of the few cytokine blockers that work for crohn's disease. There's another TNF-alpha blocker that's called etanercept, that doesn't work for crohn's disease, inflixmab can induce apoptosis of activated leukocytes (white blood cells), how it goes from blocking TNF-alpha to causing apoptosis of white blood cells I don't understand.

Tesscorm said:

Also wondering, in normal situations, the inflammatory response is part of the healing process, if remicade is indeed lessening all-over inflammatory response, could this be a factor to the increased occurrances of his shoulder pain?

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Healing normally happens after the inflammatory process, during the inflammatory process it's hard to start healing since there's usually a lot of NO and other issues that destroy tissue together with bacteria, and first the inflammation has to stop. NO production and the oxidative stress the intestine are in is probably why there's actual damage to the intestine, it destroys the epithelial cells. The leukocytes and cytokine that cause inflammation simmer down, they stop releasing cytokine, they die down because of their short lifespan, or they die through controlled apoptosis, then the healing starts. In crohn's disease it doesn't stop, the inflammatory process keeps going, something keeps triggering inflammation.

If TNF-alpha is directly involved in healing I don't know, it's mostly a cytokine that signals other leukocytes and it's involved in fever during inflammation. I think transforming growth factor cytokine are more involved in healing like TGF beta 1, many people study TGF beta 1 because too much of it results in fibrosis, and too little of it means wounds don't heal.

Unless something is wrong, wounds should heal fine while on infliximab, it's not going to stop the healing process, unless there's infection, which would prevent proper clearance of bacteria. TB / fungi infections, would be reason.

It's also not so much viral infections that people should worry about for TNF-alpha blockers, it's more bacterial I think, mostly things related to T cell.

rygon said:

Ive always found injuries to take ages to heal, and if bad enough are never quite right again. This is even before I was put on remicade (2years ago). Bones normally heal quickly but muscles and tendons are notorious for healing slowly

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people with crohn's disease have slower healing wounds, that's the basis of the theory that there are immunodeficiencies in crohn's disease

the best study of this is one where they made small wounds in people's forearm with sandpaper, they infected it with E Coli, and timed what happened

people with crohn's disease took far longer to heal than controls

Thanks for all the info Kiny!!

As my son would say You Rawk! (why they spell it that way I don't know) but it is a high compliment

Who knows what they say or mean?!?!? :ywow: When Stephen was talking about going to yoga yesterday, his text said 'yoga is gonna be sooo clutch'. What the heck does that mean??? I assumed 'clutch' was a good thing and responded 'yeah, it'll be sick!' LOL because apparently something that is 'sick' is also a good thing! :ybatty:

Haha! Did he respond when you said "it'll be sick."? I am forbidden to speak teen lingo, at every attempt I am thwarted with the most dramatic eyeroll!!

Ya, I'm with you there... so I do it all the time just to get the reaction

Here too! :lol: But, usually, by the time I figure it out, it's no longer clutch or sick nor rawking anyway!

As I understand it, the TNF-alpha blockers work through the whole body. Hence the concern over serious infections developing, it's blocking the action and therefore effectiveness of the immune system. I think of it as mopping up all the extra TNF-alpha his immune system is incorrectly producing, but probably not all of it, enough to keep him at normal levels and health. It is not an anti-inflammatory in the same sense as prednisone, I wouldn't think it would have either a positive or negative effect on his shoulder, but who knows for sure?

My teens say I use the word "awesome" too much. Guess it shows my age. I should try this new word I learned here; Clutch!! Thought that was a peddle in a car when you shift...but who am I to say

Tess, funny I have been running through this question with methotrexate. Ryan had ear surgery and I was wondering if the injection would hamper the healing process any. I wish I could remember the site where I read it, but you are on the right track. Inflammation is part of the healing process and when inflammation is taken away it alters the healing process. I would imagine that the same would be true of any medicine that fights inflammation.

Doesn't IBD kids make too much tnf- 'inflammation makers' -in their bodies...therefore too much inflammation. The tnf blocker binds up some...not all, therefore resulting in bodies like others. So I always thought of tnf blockers as 'making them closer to like normal'. So they should still be able to make inflammation when needed to heal, etc because the tnf blocker isn't taking away tnf completely. (That would be bad!)

yeah, I'm still a bit confused as to how it all works :ywow: I need to reread Kiny's posts above and research some of the words :lol: As Kiny said above, not all TNF-alpha blockers work for crohns so does that mean remicade is more systemic than some of the others (not implying this is bad though) and, if yes, then I would think this would affect inflammation other than just crohns-related inflammation. This would make sense as remicade is also used for RA, isn't it? And, so many here have said joint pain disappears when their flare is under control - but is that because the crohns directly caused the joint inflammation so, once under control, stopped 'causing' the joint pain or is it simply because the meds (remicade) turned down the inflammation at both sites (intestinal and joints).

I am going to watch for a connection... S's shoulder is still hurting and that's a bit unusual because when it hurts, it usually does so for only a couple of days. He has his next infusion on Friday... so we'll see how it goes.

Now, I'm wondering if it's possible that his shoulder pain is an indication of GI inflammation (ie higher levels of inflammation from his GI tract impacting an already vulnerable part of the body)??? He doesn't have very many outward signs of crohns directly, I wonder now if the spurts of shoulder pain could have been related to spurts of GI inflammation (but can crohns 'flare' for only a couple of days?? And, again, his pain isn't in the joint.) If it hurts until Friday and then suddenly gets better after his infusion, would really make me start believing it's somehow related???

My hubby will have a couple of day flare and then feel fine, has been going on for many years. At least that is what we've always assumed was it. We have not experienced it with Jack though

Brian'sMom said:

Doesn't IBD kids make too much tnf- 'inflammation makers' -in their bodies...therefore too much inflammation. The tnf blocker binds up some...not all, therefore resulting in bodies like others. So I always thought of tnf blockers as 'making them closer to like normal'. So they should still be able to make inflammation when needed to heal, etc because the tnf blocker isn't taking away tnf completely. (That would be bad!)

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The TNF-alpha release is normal in people with crohn's disease afaik. There's a lot more TNF-alpha in the intestine in people with crohn's disease, but that doesn't mean there's something wrong with the production of TNF-alpha.

People with crohn's disease have immunodeficiencies. Proper function of NOD2 and ATG16L1 are needed to have correct clearance of bacteria, if they're mutated or if there are other immunodeficiencies like autophagy deficiencies, you can't properly deal with bacteria and you would have a non-stop immune response.

I think a lot of people and doctors say that people with crohn's disease have "an overreactive immune system" that's never been shown, the reverse has been shown many times, people with crohn's disease are immune deficient.

People with intestinal tuberculosis who aren't treated in poorer countries can have inflammation in their intestine for years, no one looks at the inflammation and says that they have too much TNF-alpha or an overreactive immune system, that would be nice if true, they could rid themselves of TB and would have lower cancer rates, but the problem is simply that they can't deal with the TB mycobacteria.

(they have a lot more TNF-alpha than other people, and a lot more inflammation, and anti-inflammatories are often given to people with intestinal infections, but the cause isn't an overproduction of TNF-alpha, the TNF-alpha is there like it's supposed to be during inflammation)



TNF-alpha blockers stop the destructive part of the inflammation, they bind to TFN-alpha, but like said, infliximab (and likely humira too) is special, in that it can induce apoptosis of activated leukocytes. Infliximab binds to TNF-alpha, but if that TNF-alpha is on the surface of a white blood cell (leukocyte) it induces apoptosis (it kills it). Why this matters for crohn's disease isn't clear, they know that's why it works since all the ones that don't induce apoptosis don't seem to work for crohn's disease. One theory is that it works like an anti-microbial, leukocytes that harbor bacteria for phagocytosis, actually get killed by the infliximab, and it destroys the bacteria with it.


And if you know that there are immunodeficiencies at the macrophage level, in the form of autophagy, why wouldn't you look for bacteria that are able to exploit this. And they do, there's a special type of E Coli for example, AIEC, that actually exploits the autophagy step of a macrophage, and it's consistently found in people with crohn's disease. Now crohn's disease starts to look a lot more like intestinal TB than an autoimmune disease, you simply have a persistant bacteria that can't be cleared because of immunodeficiencies. So why not kill those bacteria and see if it works...well AIEC and other bacteria that could be involved in croh's disease are very nasty kinds, they tend to live in biofilms, they tend to inflitrate macrophages like a trojan horse and replicate inside them (that's why infliximab might be killing them, they destroy their trojan horse, the activated macrophage). That's why some studies use antibiotics for crohn's disease, because the theory that it's a persistent infection that can't be cleared because of immunodeficiencies "makes sense". There's 2 camps in crohn's disease, one who believe in the persistent infection and the other who believe in an uncontrolled self-targeted immune response directed towards the gut flora, I believe in the infection theory.

You could also ask yourself, if it's true that people with crohn's disease are immunodeficient, wouldn't be giving them medication that suppresses the immune system be a really really bad idea.


And people did and do ask that question:

http://www.ncbi.nlm.nih.gov/pubmed/16503465




Immunosuppressants stop the inflammation, but giving it to people who are immunocompromised isn't the smartest of ideas, but you can argue that it's better than letting the destructive inflammation go on, and agents like infliximab might be acting like anti-bacterial agents, which is paradoxial, because it actually makes things like tuberculosis worse, which is why people need the mantoux test before they're allowed to go on infliximab.

Kiny, You are so smart! I was given a link to a thread Malgrave posted some stuff on Crohns and immunodeficiency stuff. I think you were on that one but I reposted it below so you'll know exactly what I'm referring to. We saw an immunologist today and he's running some tests on Brian (because I ran across some stuff Malgrave posted on her son. My brother is deficient in IGG and gets infusions monthly-but he has a lot of respiratory stuff). Immunologist thinks just stick with the meds we're on if its crohns vs IVIG, but we should rule out what my brother has so we know its not that. But he also said tests could be skewed because of the immunosuppressant meds my son is on. But what you said above is the big problem I keep having in my head. Why put Brian on mtx when he's already having immune problems. That's the very reason I hated Aza. I feel like the GI's aren't really helping my son, just 'getting us by'. Am I thinking this all wrong? I'm going to have to read the above post over a few times as I'm not as smart as you!! The other part is the combo of Humira and Mtx seems to be making my son better. I'm confused and my GI doesn't seem to like when I bring in all kinds of research. She knows remicade and humira and combo-ing them with 6mp or mtx.

Here's the link: http://www.crohnsforum.com/showthread.php?t=43355

Fascinating, it's always been my instinct that the it is an immune deficiency. My son was constantly sick when very little and now his immune system is revved up. I'm very interested in how the clinical trial turns out for site specific immunomodulators http://www.qubiologics.com/technology/about-ssis

The SSI's are exciting stuff!

http://globalnews.ca/news/606100/new-clinical-trial-for-Crohn's-disease/

Crohn's is a misdirected/confused immune response -- it's overactive in some areas (attacking our own cells) and underactive in others (slower wound healing, etc.) As Kiny pointed out, TNF-alpha blockers such as Remicade stop a part of the inflammatory cascade that results in Crohn's symptoms.

The way Remicade works is that it's a "designer" antibody built to attach to the TNF-alpha molecule and flag it as unwanted so that the immune system will destroy it. It is very highly targeted. If you think of the immune response as a domino effect, Remicade removes one very specific domino early in the process so that it can't hit the dominos after it. It stops the inflammatory process from getting beyond the early stages.

Remicade works well in a significant chunk (but not all) of the population with Crohn's, but not in everyone (not everyone "responds" to it).

Also, there are other inflammatory pathways that do not involve TNF-alpha, at all, so Remicade doesn't work on those. For instance,it has pretty much no effect on inflammation caused by allergic responses, whereas less targeted immune suppressants, such as steroids, are great for controlling the symptoms of allergies and asthma. (Think of steroids as a hand or something holding a huge number of dominos in place, protecting them from the effect of being hit by other dominos). (It's more complicated than that in real life, obviously!)

Finally, Remicade's actions are not restricted to the intestine. When you get Remicade, it goes throughout your body. It acts wherever TNF-alpha is being produced. Many people on this forum, for instance, have extraintestinal manifestations of Crohn's (rashes, arthritis, eye symptoms, ulcers, etc.) and it can control these.

Hope this helps!

Kiny and Sickofcrohns and anyone else- How do you guys explain on how the mtx/6mp/aza combo all work? Why does it seem to 'enhance' Humira or Remicade? Is it just lowering your immune system as a whole so your body doesn't 'fight' or 'interfere' with with what the biologic is trying to do or does it help in itself? (I hate that we had to add it...but my son's labs yesterday show his inflammation (SED) finally dropping substantially after 8 weeks of adding mtx. His CRP is back to normal. So it seems to be doing good for him.) But I noticed his white blood cell count is 5.9 it used to be around 8 or 9. That makes me worry.

Not sure, what I think is interesting about 6mp is that just like remicade it can induce apoptosis. I believe, like some other people do, that 6mp and remicade are anti-microbial agents in people with crohn's disease.

this is an immune cell invaded by AIEC bacteria, if you can bind to it and can cause apoptosis (cell death), you have an immunossuppressant that functions like an antibiotic

normally this macrophage should be able to rid itself of the bacteria, unless it's acting like an APC, antigen presenting cell, and with normal bacteria this also happens

Except with a select few, AIEC is one of them MAP is another, they will penetrate a macrophage and replicate in it, they will circumvent autophagy and become a trojan horse of the immune system, they exploit the immune system

That's likely why all antibiotics that can't penetrate a macrophage don't seem to work that well for crohn's disease, only things like cipro, azithromycin, clarithromycin, are somewhat effective in crohn's disease.

I don't believe in the idea that our immune system is attacking our gut flora, and that 6mp is lowering the immune system, somehow resulting in remissions. People who are very immunocompromised still have crohn's disease and don't seem to get any better, I think 6mp is an anit-microbial. I also don't think fecal transplants or modulation of the gut flora is very beneficial, these bacteria are intracellular.

They have passed the gut wall, that's probably why unlike UC, crohn's disease is transmural, AIEC and some other candidates can penetrate deep inside the intestine.

I'm not sure how the combo works together. I kind of think they fill the holes of the other since they work differently, a two-sided attack. It seems like the 6mp is lowering the overall immune production so that the Humira is a sufficient strength to control the immune excess.. Humira wasn't enough alone for Alex, all symptoms and most bloodwork was good, but his protein and calcium were stubbornly low until a few months after adding 6mp. We'll see what happens in the fall when we drop 6mp and bump him to the adult dosage of Humira. I'm just relieved the combo IS working!