Remicade anti-TNF therapy has not yielded expected declines in hospitalisation and intestinal resection rates in inflammatory bowel diseases
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kiny
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Crohn's disease is an immunodeficiency state where the innate immune system (especially the macrophages in the intestine) are unable to clear luminal content that has entered the intestinal wall. The initial lack of secretion of inflammatory cells, causes a chronic response from the adaptive immune system, T cells are chronically being recruited by APC like dendritic cells.
What remicade (and all other anti-inflammatory medication used for CD) does is block that secondary immune response.
This leads to lowering of inflammation. But the problem is that lumen content (mostly from the fecal stream) that has entered the intestinal wall, is now not cleared at all, because medication is actively blocking the immune response.
Infliximab never used to be chronically administered in the past, it was used a single time to stop inflammation. If you chronically administer infliximab like they do now, you are just going to stimulate the underlying lesions over time.
''The Lancet, 2006 Feb
Department of Medicine, University College London
Defective acute inflammation in Crohn's disease: a clinical investigation.
INTERPRETATION:
In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.''
What remicade (and all other anti-inflammatory medication used for CD) does is block that secondary immune response.
This leads to lowering of inflammation. But the problem is that lumen content (mostly from the fecal stream) that has entered the intestinal wall, is now not cleared at all, because medication is actively blocking the immune response.
Infliximab never used to be chronically administered in the past, it was used a single time to stop inflammation. If you chronically administer infliximab like they do now, you are just going to stimulate the underlying lesions over time.
''The Lancet, 2006 Feb
Department of Medicine, University College London
Defective acute inflammation in Crohn's disease: a clinical investigation.
INTERPRETATION:
In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.''
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kiny
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The treatment in the West is much too reliant on immune suppression instead of fecal stream diversion (like one does as standard care in Japan). Chronic immune suppression leads to chronic disease.
Instead of trying to limit bacterial load in the intestine with fecal diversion and target AIEC with bacteriophages, Western doctors are preoccupied with the microflora and Western governments are spending billions on researching the microflora. Those billions have not helped one single person with crohn's disease.
Reducing the lumen content and lowering the bacterial load is why the intestine heals when you divert the fecal stream. Phagocytes, APC, and NK cells are no longer overwhelmed by a fecal stream with a high bacterial load, and the inflammation subsides because APC don't have to chronically initiate a T cell response.
(I argued that micriobiota transplantation would fail and make crohn's disease worse because you are introducing a fecal stream. Not surprisingly it worsens crohn's disease, to the surprise of doctors, but not to the surprise of researchers. ''The risk of inflammatory bowel disease flares after fecal microbiota transplantation, Qazi T et al. ...worsening in IBD activity (4.6%, (95% CI: 1.8-11%). )
If you block the adaptive immune response and target cytokine that help control that response, you simply get a stronger and stronger chronic response from the body and a build-up of bacterial content in the intestine that is no longer being removed. The body eventually builds antibodies or infliximab simply stops working. Now patients have a lot of bacterial content in their intestine and of course many people simple relapse with worsening inflammation than before they started treatment.
The way immunesuppressants are used is irresponsible. They need to be used in acute phases, they should never be used chronically, because it will lead to chronic and worsening disease.
(Using immunosuppresants to lower acute inflammation is not new, it helps during infections to lower necrosis of tissue and lower nerf damage. It is stopped of course, because you don't want to hinder the body's immune system to clear the bacteria. It isn't stopped in crohn's disease, because doctors refuse to read scientific papers.)
Instead of trying to limit bacterial load in the intestine with fecal diversion and target AIEC with bacteriophages, Western doctors are preoccupied with the microflora and Western governments are spending billions on researching the microflora. Those billions have not helped one single person with crohn's disease.
Reducing the lumen content and lowering the bacterial load is why the intestine heals when you divert the fecal stream. Phagocytes, APC, and NK cells are no longer overwhelmed by a fecal stream with a high bacterial load, and the inflammation subsides because APC don't have to chronically initiate a T cell response.
(I argued that micriobiota transplantation would fail and make crohn's disease worse because you are introducing a fecal stream. Not surprisingly it worsens crohn's disease, to the surprise of doctors, but not to the surprise of researchers. ''The risk of inflammatory bowel disease flares after fecal microbiota transplantation, Qazi T et al. ...worsening in IBD activity (4.6%, (95% CI: 1.8-11%). )
If you block the adaptive immune response and target cytokine that help control that response, you simply get a stronger and stronger chronic response from the body and a build-up of bacterial content in the intestine that is no longer being removed. The body eventually builds antibodies or infliximab simply stops working. Now patients have a lot of bacterial content in their intestine and of course many people simple relapse with worsening inflammation than before they started treatment.
The way immunesuppressants are used is irresponsible. They need to be used in acute phases, they should never be used chronically, because it will lead to chronic and worsening disease.
(Using immunosuppresants to lower acute inflammation is not new, it helps during infections to lower necrosis of tissue and lower nerf damage. It is stopped of course, because you don't want to hinder the body's immune system to clear the bacteria. It isn't stopped in crohn's disease, because doctors refuse to read scientific papers.)
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kiny
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Crohn's disease should be treated like Chronic granulomatous disease, also an innate immunodeficiency disease.
Crohn's disease is nothing like UC, has nothing to do with UC and should not be treated like UC. People with UC don't have any immunodeficiency, they respond completely normal to infection, it is very very unlikely that UC is related to an inability to clear intestinal bacteria, the immune response to bacteria is completely normal in UC. Wound healing, blood flow and immune response is completely normal.
The immune response to an infection such as E Coli is completely abnormal in crohn's disease patients, Crohn's disease is related to a very serious immunodeficiency of macrophages. Macrophages of crohn's disease patients secrete far too few cytokine like TNF-α. There is also a general lack of blood flow. Crohn's disease patients have an incredibly immunodeficient innate immune system, the adaptive response is completely normal however, but a lack of cytokine secretion by macrophages (TNF, IL-1, etc) will result in a delayed and inappropriate response. (the basis for this is of course genetic predisposition link in crohn's disease)
Segal AW, Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity.
UC patients respond to bacterial infection like healthy controls. There is no difference, UC has nothing to do with bacterial infection, it is doubtful it has anything to do with bacteria at all.
However, Crohn's disease patients fail to clear bacteria properly and a persistent inflammation occurs. The innate immune response of macrohages is completley insufficient in crohn's disease patients.
Andrew M. Smith
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease
Again, completely normal response to bacterial infection in UC and Healthy Control, completely insufficient clearance in CD.
Just like CGD (chronic granulomatous disease), crohn's disease is an innate immunodeficiency (primarily of intestinal macrophages in crohn's disease), that results in a cascading adaptive immune response, specifically the cell-mediated immune response due to bacteria, fungi and fecal content that enter through the intestinal epithelial barrier that can't be cleared.
You don't treat primary immunodeficiency diseases with chronic immune suppression, because it often leads to more and more inflammation and bacterial load over time. It should be used to treat acute inflammation, and that's how infliximab used to be used, until they started using it chronically, which isn't a solution.
Crohn's disease is nothing like UC, has nothing to do with UC and should not be treated like UC. People with UC don't have any immunodeficiency, they respond completely normal to infection, it is very very unlikely that UC is related to an inability to clear intestinal bacteria, the immune response to bacteria is completely normal in UC. Wound healing, blood flow and immune response is completely normal.
The immune response to an infection such as E Coli is completely abnormal in crohn's disease patients, Crohn's disease is related to a very serious immunodeficiency of macrophages. Macrophages of crohn's disease patients secrete far too few cytokine like TNF-α. There is also a general lack of blood flow. Crohn's disease patients have an incredibly immunodeficient innate immune system, the adaptive response is completely normal however, but a lack of cytokine secretion by macrophages (TNF, IL-1, etc) will result in a delayed and inappropriate response. (the basis for this is of course genetic predisposition link in crohn's disease)
Segal AW, Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity.
UC patients respond to bacterial infection like healthy controls. There is no difference, UC has nothing to do with bacterial infection, it is doubtful it has anything to do with bacteria at all.
However, Crohn's disease patients fail to clear bacteria properly and a persistent inflammation occurs. The innate immune response of macrohages is completley insufficient in crohn's disease patients.
Andrew M. Smith
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease
Again, completely normal response to bacterial infection in UC and Healthy Control, completely insufficient clearance in CD.
Just like CGD (chronic granulomatous disease), crohn's disease is an innate immunodeficiency (primarily of intestinal macrophages in crohn's disease), that results in a cascading adaptive immune response, specifically the cell-mediated immune response due to bacteria, fungi and fecal content that enter through the intestinal epithelial barrier that can't be cleared.
You don't treat primary immunodeficiency diseases with chronic immune suppression, because it often leads to more and more inflammation and bacterial load over time. It should be used to treat acute inflammation, and that's how infliximab used to be used, until they started using it chronically, which isn't a solution.
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kiny
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Hi, I read the site. Not going to comment on the medication, I don't know how it works.
What they write is true.
It's true that Crohn's disease needs to be treated from a primary immunodeficiency standpoint, that should be the focus
I don't think the adaptive response is abnormal, it is delayed, but not abnormal. The adaptive immune system is simply responding to the (insufficient) secretion of TNF by macrophages and APC will keep triggering the adaptive immune system. The primary response is insufficient, the secondary response become chronic because macrophages failed to clear bacterial content that constantly invades the intestinal wall.
I also don't think it matters how crohn's disease is initiated. I think it's due to an initial infection. Many crohn's disease patients have nightsweats, fevers, and sometimes throw up early on. They got infected by a food borne infection, listeria, salmonella, yersinia or campylobacter. That infection left the intestine permeable, and bacteria and fecal content now chronically activating the immune system, which is why there is chronic inflammation. Because the immune system can't clear the bacteria, your inflammation persists. Removing the fecal stream or limiting it of course helps and lowers inflammation. I don't think the initial infection is still there either, it has long been cleared.
I agree with what they write, just not all specifics, but I don't think those specifics matter for crohn's disease patients, it doesn't matter how the disease is initiated years ago to current patients. (it matters to avoid new cases of crohn's disease, and it's important, but it doesn't matter or affect me personally so I don't focus too much on that) What matters is how to maintina remission. .
What they write is true.
It's true that Crohn's disease needs to be treated from a primary immunodeficiency standpoint, that should be the focus
I don't think the adaptive response is abnormal, it is delayed, but not abnormal. The adaptive immune system is simply responding to the (insufficient) secretion of TNF by macrophages and APC will keep triggering the adaptive immune system. The primary response is insufficient, the secondary response become chronic because macrophages failed to clear bacterial content that constantly invades the intestinal wall.
I also don't think it matters how crohn's disease is initiated. I think it's due to an initial infection. Many crohn's disease patients have nightsweats, fevers, and sometimes throw up early on. They got infected by a food borne infection, listeria, salmonella, yersinia or campylobacter. That infection left the intestine permeable, and bacteria and fecal content now chronically activating the immune system, which is why there is chronic inflammation. Because the immune system can't clear the bacteria, your inflammation persists. Removing the fecal stream or limiting it of course helps and lowers inflammation. I don't think the initial infection is still there either, it has long been cleared.
I agree with what they write, just not all specifics, but I don't think those specifics matter for crohn's disease patients, it doesn't matter how the disease is initiated years ago to current patients. (it matters to avoid new cases of crohn's disease, and it's important, but it doesn't matter or affect me personally so I don't focus too much on that) What matters is how to maintina remission. .
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kiny
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(I also don't think it's helpful to lump crohn's disease and UC together. I have said many times these two disease are unrelated. What you see in crohn's disease is what you see in chronic granulomatous disease. Crohn's disease needs to be classified and treated as a primary immunodeficiency of macrphages. Response to bacteria is normal in UC, it is not normal in crohn's disease.
Hopefully they also stop wasting billions on microbiome research. 10 years of research that has never helped a single person with crohn's disease. The immune system in crohn's disease is clearly being triggered by the fecal stream which is high in bacterial load, and a handful of bacteria and fungi, not by harmless commensal bacteria.
If you give people with crohn's disease fecal transplants, they get worse, niether have probiotics ever helped.
If you instead remove the fecal stream with parental or elemental nutrition instead, the intestine heals of course, since you removed or limited the fecal stream, which lowers the bacterial load, and which lowers the load on the compromised immune system in crohn's disease.)
Hopefully they also stop wasting billions on microbiome research. 10 years of research that has never helped a single person with crohn's disease. The immune system in crohn's disease is clearly being triggered by the fecal stream which is high in bacterial load, and a handful of bacteria and fungi, not by harmless commensal bacteria.
If you give people with crohn's disease fecal transplants, they get worse, niether have probiotics ever helped.
If you instead remove the fecal stream with parental or elemental nutrition instead, the intestine heals of course, since you removed or limited the fecal stream, which lowers the bacterial load, and which lowers the load on the compromised immune system in crohn's disease.)
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kiny
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While I'm ranting. The innate immune response is very abnormal, but the adaptive response is normal. In the intestine of crohn's disease patients there are normal levels of T4 and T8. The thymus works normal in crohn's disease.
It becomes abnormal once people with crohn's disease are on chronic immunsuppressants. You see CD4 drop dramatically and you see Lymphopenia as a side effect of inflixmab treatment. Which of course impact the disease because you need CD4 helper cells if you want phagocytes to destroy microbes. It takes a long time before the immune system recovers from chronic immunosuppressive therapy.
David
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I'm so pleased to see you back @kiny -- your knowledge has obviously improved dramatically.
I was going to ask if your statement of, "Removing the fecal stream or limiting it of course helps and lowers inflammation" is why so many do well with enteral nutrition but you shared that two posts above. Is entertal nutrition the primary treatment option in Japan?
I was going to ask if your statement of, "Removing the fecal stream or limiting it of course helps and lowers inflammation" is why so many do well with enteral nutrition but you shared that two posts above. Is entertal nutrition the primary treatment option in Japan?
kiny
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Hi David.
Yes and yes. Adults are routinely put on EN in Japan. Fecal stream diversion and limiting the fecal stream is an important but neglected therapy in the West, especially for adults. The fecal stream evokes chronic inflammation, if you remove the fecal stream the inflammation subsides.
The reason EN works is because it simply limits the fecal stream, EN has high bioavailability. It does not work because there is something particular in EN, not because it changes the composition of the microbiome (it does, but that's normal after inflammation subsides), it simply works because it lowers fecal content.
Segal AW, Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity.
David
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Which would explain why many on juicing diets do well as well.
Many have reported improvement with paleo and SCD diets. Do you think there could be something in that fecal stream from western diets that may be the underlying cause? And those diets either don't negatively affect something with the innate immune system OR don't allow certain bacteria to proliferate?
Many have reported improvement with paleo and SCD diets. Do you think there could be something in that fecal stream from western diets that may be the underlying cause? And those diets either don't negatively affect something with the innate immune system OR don't allow certain bacteria to proliferate?
David
Co-Founder
Kiny, do you think those who take immunosuppressants long term still have the opportunity to benefit from fecal stream diversion or is the damage already done?
I know Qu Biologics sees the best result in those who have not taken biologics.
I know Qu Biologics sees the best result in those who have not taken biologics.
kiny
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The initial cause is probably an infection. Either with a foodborne bacteria like yersinia or listeria, or salmonella or campylobacter.
People who have had a salmonella or campylobacter infection are far more likely to develop crohn's disease after. https://www.ncbi.nlm.nih.gov/pubmed/19361507
This explains why people who develop crohn's disease suffer from high fevers, night sweats, they tend to throw up before diganosis, it all points to food borne bacteria and infections.
This infection likely subsides, but it leaves a permeable bowel behind. That permeable bowel is then chronically being invaded by bacterial content from the fecal stream, and certain bacteria like AIEC, fungi, and others, exploit a chronic inflammatory environment.
(this results in dysbiosis, but this is not the reason for the inflammation, it is a secondary event, intestinal inflammation lead to dysbiosis)
Due to macrophage deficiencies, the intestine can not properly clear the high bacterial load in the intestine, it is especially difficult with a high bacterial load from the fecal stream. In a second phase,the innate immune system then chronically stimulates the adaptive immune and
antigen-presenting cell keep recruiting lymphocites, and you get cascading inflammation.
If diets have a beneficial impact, it is probably because they are low residue and reduce fecal matter. SCD removes complex carbohydrates which would increase the bioavailability of the diet. I don't think they have any effect on the innate immune system, nor that they have a significant effect on bacterial composition in the lumen.
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Kiny, I think a few corrections/elaborations are needed for your posts. I am currently in a hospital bed, with a picc line on my right hand. First, I am dropping this thread from HW. My nickname is xy123 there.
https://www.healingwell.com/community/default.aspx?f=38&m=4044862
I will write with my left hand on my iPad, it will take some time.
https://www.healingwell.com/community/default.aspx?f=38&m=4044862
I will write with my left hand on my iPad, it will take some time.
kiny
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Yes, the goal should be to limit fecal content in the intestine so the bacterial load at the epithelial barrier is reduced.
I understimated the permeability of the intestinal epithelial barrier in the past. Mucosal healing does not mean the bowel is no longer permeable, a bowel is very permeable and fecal matter is a constant threat to the integrity of the mucus layer and intestine. The intestine is lined from top to bottom with macrophages to rid the intestine of bacterial content, crohn's disease inflammation can be deep and transmural. The intestine is the main point of entry for bacteria.
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There are other and very important possible reasons for the initiation and the chronicity of the intestinal permeability problem other than microorganisms. Some examples are the immunogenicity of the foods and liquids we consume, endocrinological state of the person (this is quite complex but the easiest you can look for is the direct relationship between elevated cortisol and the increased intestinal permeability), the energy metabolism of the person etc.
Fully elemental EN works, because it is not fermentable (massive reduction in the microbial load) AND it doesn’t contain immunogenic substances like casein; unlike non-fully elemental EN like modulen, which is casein based. Even if, theoretically, you get a sterile gut, if you keep putting immunogenic substances on your mouth and swallow, the inflammation will continue, though it will still be decreased a lot because of the non-existence of the microorganisms.
Fully elemental EN are amino acid based.
I agree that claims and speculations about good and bad bacteria are bogus. Microbiota topic is highly complex with its interrelations with each other, the host, the environment, epigenetics etc. And the current knowledge about the topic is almost nil - compared to what needs to be known.
Surgical diversion of the intestines is also effective, for the same reason: limiting the microorganism growth and stopping the immunogenic foods’ stream, also toxins in our foods, drinks etc. Not surprisingly, often quickly after the reversal of the diversion (anastomosis), crohns returns in patients.
Edit: fully elemental EN is quickly, efficiently and easily absorbed in the small intestines. That’s what I mean by the “not fermentable”. Compare it with starch for the fermentability issue. By the way, because of these, your nutritional and hormonal state, and energy metabolism improve from fully elemental EN. Which are also relevant mechanisms.
Edit 2: also, with the exclusion of hard, irritating, fermentable foods, intestinal serotonin decreases a lot. This is also relevant for the inflammation, functionality, healing. People with Crohns have elevated serotonin in their intestines.
Fully elemental EN works, because it is not fermentable (massive reduction in the microbial load) AND it doesn’t contain immunogenic substances like casein; unlike non-fully elemental EN like modulen, which is casein based. Even if, theoretically, you get a sterile gut, if you keep putting immunogenic substances on your mouth and swallow, the inflammation will continue, though it will still be decreased a lot because of the non-existence of the microorganisms.
Fully elemental EN are amino acid based.
I agree that claims and speculations about good and bad bacteria are bogus. Microbiota topic is highly complex with its interrelations with each other, the host, the environment, epigenetics etc. And the current knowledge about the topic is almost nil - compared to what needs to be known.
Surgical diversion of the intestines is also effective, for the same reason: limiting the microorganism growth and stopping the immunogenic foods’ stream, also toxins in our foods, drinks etc. Not surprisingly, often quickly after the reversal of the diversion (anastomosis), crohns returns in patients.
Edit: fully elemental EN is quickly, efficiently and easily absorbed in the small intestines. That’s what I mean by the “not fermentable”. Compare it with starch for the fermentability issue. By the way, because of these, your nutritional and hormonal state, and energy metabolism improve from fully elemental EN. Which are also relevant mechanisms.
Edit 2: also, with the exclusion of hard, irritating, fermentable foods, intestinal serotonin decreases a lot. This is also relevant for the inflammation, functionality, healing. People with Crohns have elevated serotonin in their intestines.
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kiny
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I don't know anything about this medication, I have simply read the site because people asked me to.
But like they said, the ideal solution would obviously be to correct the primary immunodeficiency. If you correct macrophage defficiencies (especially the lack of TNF secretion) you could treat the disease proactively, instead of reactively.
Stimulation of the innate immune response has been tried before with success in crohn's disease.
Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor.
https://www.ncbi.nlm.nih.gov/pubmed/12433518
If it wasn't for the fact that Chronic granulomatous disease is rather rare, Crohn's disease and Chronic granulomatous disease with intestinal involvement, would be incredibly hard to dintinguish. In fact, people with Chronic granulomatous disease, not surprisingly, have very high rates of Crohn's disease. So do people with Blau syndrome.
kiny
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No, bacteriophages need to be specifically selected or modified before they are useful.
I don't doubt that product contains bacteriophages, because pretty much everything contains bacteriophages. The mucus layer in the intestine is full of bacteriophages, so is the human skin. Everywhere where there are bacteria, there are bacteriophages, if it wasn't for bacteriophages, life would quickly succumb to bacteria.
But no, that products is not helpful in any way, nor do I recommend anyone taking it.
What we will see is specifically designed bacteriophages that target specific bacteria found in crohn's disease. It will hopefully lead to more personalised therapy, where a stool sample or biopsy serves as a guideline to determine which bacteriophage might be useful.
https://www.ncbi.nlm.nih.gov/pubmed/28130329
There are currently ongoing trial underway with bacteriophages to treat crohn's disease. It might be helpful in people who harbour invasive E coli.
What the benefit of bacteriophages is over antibiotics is of course their specificity, the fact they don't have any known side effects, and unlike antibiotics they don't suffer from resistance.
Broad spectrum antibiotics that are used currently, have no such specificity, and they create resistance.
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This is the current study. It’s interesting.
I thought supplementing the above product (on amazon) every day could reduce bacterial load, thus reduce intestinal inflammation; but I think you are saying the phages have always a much narrower spectrum, therefore it won’t be very useful - unlike antibiotics.
I thought supplementing the above product (on amazon) every day could reduce bacterial load, thus reduce intestinal inflammation; but I think you are saying the phages have always a much narrower spectrum, therefore it won’t be very useful - unlike antibiotics.
kiny
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It's quite difficult for people and even doctors, to wrap their heads around crohn's disease being an innate immunodeficiency state.
''if it is an immunodeficiency state, why is there all this inflammation?''
What happens in an immunocompetent person who doesn't suffer from immunodeficiency is something like this....
...this is how a normal reaction takes place in an immunocompetent person:
00:00
1) the epithelial barrier was compromised, a bacteria has entered through the epithelial barrier (main entry points of the body for bacteria are the skin, intestine and lungs)
00:00-6 hours
2) phagocytes like macrophages and NK cells waiting behind the epithelial barrier mount the primary immune response, macrophages start to secrete cytokine
3) if the bacteria was not killed by the initial macrophage response (a tuberculosis infection for example), the much slower but much more competent and specific adaptive immune system is called upon
12 hours later
4) dendritic cells from the innate immune system form the link between the innate and adaptive immune system, they migrate to the lymph nodes and contact T cells, they do this by presenting antigen (they are antigen-presenting cells), T cells are now activated and mount the adaptive response
1 day later
5) T cells have now recognized the bacteria thanks to antigen presentation, they migrate to the bacteria, they activate macrophages and order them to kill phagocytosed microbes, other T cells kill infected cells to destroy intracellular microbes
2 days later
6) the invader is defeated, some immune cells were killed, some survived and will serve as memory cells, the inflammation subsides
The problem with crohn's disease is that first of all, that the epithelial barrier is compromised. The second problem is that innate response is insufficient, bacterial content is not properly cleared, crohn's disease is a primary immunodeficiency disease, and the result is that the adaptive immune system is chronically activated which leads to chronic inflammation.
''if it is an immunodeficiency state, why is there all this inflammation?''
What happens in an immunocompetent person who doesn't suffer from immunodeficiency is something like this....
...this is how a normal reaction takes place in an immunocompetent person:
00:00
1) the epithelial barrier was compromised, a bacteria has entered through the epithelial barrier (main entry points of the body for bacteria are the skin, intestine and lungs)
00:00-6 hours
2) phagocytes like macrophages and NK cells waiting behind the epithelial barrier mount the primary immune response, macrophages start to secrete cytokine
3) if the bacteria was not killed by the initial macrophage response (a tuberculosis infection for example), the much slower but much more competent and specific adaptive immune system is called upon
12 hours later
4) dendritic cells from the innate immune system form the link between the innate and adaptive immune system, they migrate to the lymph nodes and contact T cells, they do this by presenting antigen (they are antigen-presenting cells), T cells are now activated and mount the adaptive response
1 day later
5) T cells have now recognized the bacteria thanks to antigen presentation, they migrate to the bacteria, they activate macrophages and order them to kill phagocytosed microbes, other T cells kill infected cells to destroy intracellular microbes
2 days later
6) the invader is defeated, some immune cells were killed, some survived and will serve as memory cells, the inflammation subsides
The problem with crohn's disease is that first of all, that the epithelial barrier is compromised. The second problem is that innate response is insufficient, bacterial content is not properly cleared, crohn's disease is a primary immunodeficiency disease, and the result is that the adaptive immune system is chronically activated which leads to chronic inflammation.
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kiny
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If crohn's disease was an ''overreactive immune system'', that would actually be great, we would be immune to infections and never get a cold during the winter.
That's sadly not what is going on. We are immune deficient, our innate immune system is unable to clear bacterial content in a correct manner, our adaptive immune system is chronically activated to compensate as a result. Stopping the adaptive immune system from activating is what immunosuppressant drugs try to do, and they work great to limit damage to the bowel initially. But they don't solve the underlying problem, they don't remove bacterial content, and if you use immunosuppression chronically, you might actually be promoting chronic disease instead.
Crohn's disease needs to be categorized as a primary immunodeficiency disease, just like Chronic granulomatous disease.
That's sadly not what is going on. We are immune deficient, our innate immune system is unable to clear bacterial content in a correct manner, our adaptive immune system is chronically activated to compensate as a result. Stopping the adaptive immune system from activating is what immunosuppressant drugs try to do, and they work great to limit damage to the bowel initially. But they don't solve the underlying problem, they don't remove bacterial content, and if you use immunosuppression chronically, you might actually be promoting chronic disease instead.
Crohn's disease needs to be categorized as a primary immunodeficiency disease, just like Chronic granulomatous disease.
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Kiny, I wondered what your thoughts were on food intolerances?
Is my thinking correct: we know that EN works because it reduces the bacterial flora - the two ways we know how to change the flora are antibiotics and diet. And if by eating a 'wrong' food, you are increasing the bacteria which then cannot be cleared from the intestinal wall and therefore causes inflammation and therefore causes symptoms - thereby allowing the patient to identify it as a 'wrong' food.
In my case, my intolerances are increasing i.e. a previously safe food is now causing issues.
What would be a logical next step? Probiotics possibly, but I just feel probiotics sit better with UC than CD.
Is my thinking correct: we know that EN works because it reduces the bacterial flora - the two ways we know how to change the flora are antibiotics and diet. And if by eating a 'wrong' food, you are increasing the bacteria which then cannot be cleared from the intestinal wall and therefore causes inflammation and therefore causes symptoms - thereby allowing the patient to identify it as a 'wrong' food.
In my case, my intolerances are increasing i.e. a previously safe food is now causing issues.
What would be a logical next step? Probiotics possibly, but I just feel probiotics sit better with UC than CD.
kiny
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It lowers bacterial load because it reduces the fecal stream and fecal retention, likely due to its high bioavailability.
Fecal content is high in bacterial load (why is smells bad, why we have aversion to it, and why we throw up if the body notices we ingested it, the body is trying to avoid you come into contact with it due to how loaded with bacteria it is)
Which bacteria are responsible for the immune response isn't known, but I kinda doubt it is commensal bacteria from the gut flora. It's possible, but it is more likely pathogenic bacteria like invasive E coli, opportunistic bactera, foodborne bacteria, fungi, etc.
If the commensal gut flora isn't directly involved in evoking the immune response, it would explain why probiotics aren't useful in crohn's disease.
That's not to say that probiotics are completely useless, bacteria compete for space in the intestine, commensal bacteria prevent adhesion of pathogenic bacteria to the intestinal wall, and they affect biofilm formation of those bacteria. But the effect of probiotis is probably extremely limited.
Antibiotics can be very useful in crohn's disease. But they come with their own problems.
Several of the antibiotics that are effective in crohn's disease and macrophage penetrating, are very broad spectrum, which might leave the patients in a worse situation.
Antibiotics create resistance, cipro is very effective against invasive E Coli but AIEC become resistant very quickly.
There's probably some foods that don't help. Avoiding maltodextrin and emulsifiers is probably a good idea. Maltodextrin will increase the growth of E Coli and emulsifiers cause bacteria to migrate into intestinal epithelia. Otherwise I don't know if diets help in any meaningful way.
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kiny
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Just to add. When research papers, especially older research papers, use the word ''crohn's disease'', they are often referring to the strict definition of crohn's disease as described by Dalziel. Chronic enteritis, inflammation of the ileum in the form of patchy granuloma.
When I say ''crohn's disease'', I too strictly mean ileal disease, with no or negligeable colon involvement. I know far more about the ileum and peyer's patches than I do about the colon.
EN has been shown to help in standard classic crohn's disease, where the disease is restricted to the ileum. It especially helps if there is stenosis present or wall narrowing, which might restrict the normal flow of regular food.
EN doesn't work nearly as well if there is colonic involvement, which makes sense, because stool forms in the colon where water is absorbed, not in the small intestine.
When I say ''crohn's disease'', I too strictly mean ileal disease, with no or negligeable colon involvement. I know far more about the ileum and peyer's patches than I do about the colon.
EN has been shown to help in standard classic crohn's disease, where the disease is restricted to the ileum. It especially helps if there is stenosis present or wall narrowing, which might restrict the normal flow of regular food.
EN doesn't work nearly as well if there is colonic involvement, which makes sense, because stool forms in the colon where water is absorbed, not in the small intestine.
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So I am following the innate immunodeficiency
-some researchers in the US feel strongly this is behind veo ibd kids (Ds has this version of crohns )
But....
If een helps calm why does inflammation come back the minute it’s stopped
Is the time period too short ???
Kids typically get 6-8 weeks of een
At least Ds has
And then he continued with 50% supplemental en (amino acid based )
He goes back to een as needed
Inflammation still comes back
Even before he started immunosuppressants of any sort
He did een first .
Ivig helps immunodeficiency
Ds tried this as well
Didn’t help either
Do adults stay on een for life ???
I know some US pediatric ibd hospitals
Use 90%een/10% food
Or
80%een/20% foid
Long term
This didn’t work for my kiddo but works for a lot of kids
-some researchers in the US feel strongly this is behind veo ibd kids (Ds has this version of crohns )
But....
If een helps calm why does inflammation come back the minute it’s stopped
Is the time period too short ???
Kids typically get 6-8 weeks of een
At least Ds has
And then he continued with 50% supplemental en (amino acid based )
He goes back to een as needed
Inflammation still comes back
Even before he started immunosuppressants of any sort
He did een first .
Ivig helps immunodeficiency
Ds tried this as well
Didn’t help either
Do adults stay on een for life ???
I know some US pediatric ibd hospitals
Use 90%een/10% food
Or
80%een/20% foid
Long term
This didn’t work for my kiddo but works for a lot of kids
kiny
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A full immune response is mounted over a few days. Lymphocytes have to recognize antigen, they expand and then effector cells eliminate the antigen.
All these steps happens over a number of days, it doesn't strike me as unreasonable that inflammation comes back within weeks, or even days, if the person drops EN. Remission isn't going to last if EN is dropped.
People do seem to relapse more slowly after stopping immunosupressants, but these powerful immmunosupressants results in a weaked immune system that takes a long time to recover. One of the common side effects of infliximab is lymphopenia for example. By the time people relapse on immunosuppressants (they all only work for a few years before people relapse), the medication has probably stopped working for a long time, it takes the immune system a while before it recovers.
The body has a whole host of mechanics to circument these type of medications and reintroduce an inflammatory response, people without antibodies to infliximab relapse too. It just takes the body a while before it understand how, but everyone relapses on infliximab after a few years, which is why this study isn't that surprising. Chronic immunosuppression isn't a long term solution, the body will find ways to circumvent the medication. And the main problem, namely bacteria getting past the intestine's epithelial barrier and not being removed by the immune system in a correct manner, isn't being dealt with, so you just stimulate chronic disease.
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kiny
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What is not widely known is that the chronic use of infliximab is not how this medication was originally used to treat crohn's disease. It was given as a one-off treatment to limit the more acute forms of inflammation.
(it also isn't known by hospitals that only started using this medication later on)
It was used to induce remission, but it wasn't a therapy to maintain remission. Treatment was stopped after one IV, and people went back to their maintenance therapy after, their corticosteroids, imuran, antibiotics, mesalamine, EN, whatever they were using as maintenance therapy back then (there wasn't a lot of choice, infliximab was the only biologic on the market).
The idea of giving people this medication every 8 or 10 weeks was introduced years after the medication had been on the market and actively used to treat crohn's disease.
When researchers started warning that chronic use of immunosupressants might lead to chronic disease, it was a response to doctors suggesting that this medication should be used chronically to avoid antibody development. The consequence of chronic use of this medication were never a problem initially, because it wasn't used chronically.
(it also isn't known by hospitals that only started using this medication later on)
It was used to induce remission, but it wasn't a therapy to maintain remission. Treatment was stopped after one IV, and people went back to their maintenance therapy after, their corticosteroids, imuran, antibiotics, mesalamine, EN, whatever they were using as maintenance therapy back then (there wasn't a lot of choice, infliximab was the only biologic on the market).
The idea of giving people this medication every 8 or 10 weeks was introduced years after the medication had been on the market and actively used to treat crohn's disease.
When researchers started warning that chronic use of immunosupressants might lead to chronic disease, it was a response to doctors suggesting that this medication should be used chronically to avoid antibody development. The consequence of chronic use of this medication were never a problem initially, because it wasn't used chronically.
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@kiny, have you seen this paper?
https://crohnsforum.com/threads/anti-map-therapy-support-group.82362/post-1020116
A review of it: https://crohnsforum.com/threads/anti-map-therapy-support-group.82362/post-1020294
"In cattle, inoculating against MAP has proved remarkably effective, according to a study published in October 2014 in Veterinary Research. The vaccine trains cows’ immune systems to kill off MAP in their guts, in many cases leading to permanent relief. The tantalizing question: Might it also work for people?"
"'If it does in humans what it did in preclinical animal trials, the vaccine could have significant benefits for people with Crohn’s disease,' Hermon-Taylor says."
From: https://www.everydayhealth.com/crohns-disease/treatment/cure-crohns-disease-how-hopeful-should-we/
This is the link to the animal study: https://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-014-0112-9
What do you think about the immunisation approach against MAP for Crohn’s?
https://crohnsforum.com/threads/anti-map-therapy-support-group.82362/post-1020116
A review of it: https://crohnsforum.com/threads/anti-map-therapy-support-group.82362/post-1020294
"In cattle, inoculating against MAP has proved remarkably effective, according to a study published in October 2014 in Veterinary Research. The vaccine trains cows’ immune systems to kill off MAP in their guts, in many cases leading to permanent relief. The tantalizing question: Might it also work for people?"
"'If it does in humans what it did in preclinical animal trials, the vaccine could have significant benefits for people with Crohn’s disease,' Hermon-Taylor says."
From: https://www.everydayhealth.com/crohns-disease/treatment/cure-crohns-disease-how-hopeful-should-we/
This is the link to the animal study: https://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-014-0112-9
What do you think about the immunisation approach against MAP for Crohn’s?
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Regarding the vet study, they gave the vaccine prior to the MAP infection in calves, and found it an effective preventative. How will this translate into treating already infected humans? Even if it stimulates the successful killing of the MAP in the patients by their immune system, will this actually help their Crohn's?
The study published by Jenner institute was done on healthy adult volunteers, and the vaccine was found to be immunogenic (look at the section 3.3. [Immunogenicity] in the paper for more information). Whether it will actually help Crohn's patients, or, more importantly, whether Crohn's is caused by MAP or not remains to be seen.
From the study article:
"The vaccine antigen consists of a fusion construct from the AhpC, Gsd, p12 and mpa MAP genes, which are present in all MAP strains. The antigen was named HAV and has been described elsewhere [34]."
"Prior to vaccination, responses to HAV antigens were low, with a geometric mean response of 109 (95% CI 79–151) spot-forming cells (SFC) per million PBMC, which increased to a geometric mean of 250 SFC (95% CI 107–583) at day 28 taking an average across all dose groups (Figure 3a).
Responses were highest at day 28 in participants immunised with 2.5 × 1010 vp and were significantly increased after vaccination only in this dose group (p < 0.05, Kruskall-Wallis test with Dunn’s multiple comparison test compared with D0 responses). Responses were detected to all antigens at day 28 with geometric mean responses ranging as follows; AhpC- 56 SFC, Gsd-41SFC, p12-64 SFC, mpa-52 SFC per million PBMC (Figure 3b)."
The study published by Jenner institute was done on healthy adult volunteers, and the vaccine was found to be immunogenic (look at the section 3.3. [Immunogenicity] in the paper for more information). Whether it will actually help Crohn's patients, or, more importantly, whether Crohn's is caused by MAP or not remains to be seen.
From the study article:
"The vaccine antigen consists of a fusion construct from the AhpC, Gsd, p12 and mpa MAP genes, which are present in all MAP strains. The antigen was named HAV and has been described elsewhere [34]."
"Prior to vaccination, responses to HAV antigens were low, with a geometric mean response of 109 (95% CI 79–151) spot-forming cells (SFC) per million PBMC, which increased to a geometric mean of 250 SFC (95% CI 107–583) at day 28 taking an average across all dose groups (Figure 3a).
Responses were highest at day 28 in participants immunised with 2.5 × 1010 vp and were significantly increased after vaccination only in this dose group (p < 0.05, Kruskall-Wallis test with Dunn’s multiple comparison test compared with D0 responses). Responses were detected to all antigens at day 28 with geometric mean responses ranging as follows; AhpC- 56 SFC, Gsd-41SFC, p12-64 SFC, mpa-52 SFC per million PBMC (Figure 3b)."
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kiny
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I think it's possible that MAP is at least partially responsible for inflammation in a subset of crohn's disease patients.
But for every argument that speaks in favor of MAP being a causative agent, there are just as many that put them in doubt.
MAP infection in cattle looks quite similar to Crohn's disease in humans. The digestive track of cattle is different than that of humans, but the part that is relevant here is the ileum, and that is not that different. Cattle feature the exact same peyer's patches as humans, the inflammation results in patchy granuloma that are exactly like you find in humans.
Genetic predisposition in crohn's disease leaves patients particularly vulnerable to mycobacteria infections. It makes sense that would leave someone very vulnerable to MAP infection.
But then there are arguments against MAP too.
Why don't farmers have higher rates of crohn's disease, they should have spectacularly higher rates of crohn's disease but they don't. Why don't people who drink lots of milk have higher rates of crohn's disease.
MAP is slow dividing and has a long incubation period in cattle, crohn's disease isn't like that, crohn's disease is rather acute, patients initially suffer from what seems to be an infection like salmonella or campylobacter, they throw up, they have acute fevers with night sweats (this later subsides, most likely because the initial infection is overcome), but those aren't symptoms of a MAP infection.
But for every argument that speaks in favor of MAP being a causative agent, there are just as many that put them in doubt.
MAP infection in cattle looks quite similar to Crohn's disease in humans. The digestive track of cattle is different than that of humans, but the part that is relevant here is the ileum, and that is not that different. Cattle feature the exact same peyer's patches as humans, the inflammation results in patchy granuloma that are exactly like you find in humans.
Genetic predisposition in crohn's disease leaves patients particularly vulnerable to mycobacteria infections. It makes sense that would leave someone very vulnerable to MAP infection.
But then there are arguments against MAP too.
Why don't farmers have higher rates of crohn's disease, they should have spectacularly higher rates of crohn's disease but they don't. Why don't people who drink lots of milk have higher rates of crohn's disease.
MAP is slow dividing and has a long incubation period in cattle, crohn's disease isn't like that, crohn's disease is rather acute, patients initially suffer from what seems to be an infection like salmonella or campylobacter, they throw up, they have acute fevers with night sweats (this later subsides, most likely because the initial infection is overcome), but those aren't symptoms of a MAP infection.
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kiny
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Improvements after administration of antibiotics cocktails that target MAP might just be lowering bacterial load instead of suppressing MAP.
One should also keep in mind that MAP is a gram positive mycobacteria that is very different from the cell wall you find in gram negative E coli and other foodborne pathogens like yersinia you often find in crohn's disease patients.
If you give those antibiotics to someone who is actually harbouring invasive E Coli, you might be creating resistance and making something that is effective against e coli, like cipro, less effective due to the resistance you created with those broad spectrum cocktails.
Before you administer those cocktails, you need to be sure that the patients harbours MAP, and that it is behind the inflammation.
One should also keep in mind that MAP is a gram positive mycobacteria that is very different from the cell wall you find in gram negative E coli and other foodborne pathogens like yersinia you often find in crohn's disease patients.
If you give those antibiotics to someone who is actually harbouring invasive E Coli, you might be creating resistance and making something that is effective against e coli, like cipro, less effective due to the resistance you created with those broad spectrum cocktails.
Before you administer those cocktails, you need to be sure that the patients harbours MAP, and that it is behind the inflammation.
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The vaccine group is very self-confident that their vaccine will be “the cure” for the majority/all crohns patients. In their estimation, at the end of this year, the clinical trial with actual crohns patients will start.
Here’s their FAQ page: http://www.crohnsmapvaccine.com/faq/
Regardless of this, the rhb-104 trial result was disappointing.
About cipro: anti-map abx combination usually consists of clarithromycin, rifabutin, and clofazimine. Cipro is very rarely used. I for one wouldn’t touch that drug, after reading and experiencing its high toxicity. For me to use it, I must have absolutely no other options. You can read many horror stories about people’s experiences with cipro online. Terrible, seemingly permanent effects.
I agree with you about the reduction of “commensal” gut bacteria (bacterial load) being the possible reason for the anti-map cocktail’s effectiveness. I wrote about it in the HW forum thread I posted above. Let’s not forget also that, antibiotics have actually anti-inflammatory effects independent of their antibacterial effects. Low dose tetracyclines’ anti-inflammatory effect is a well known example. This is also a possible mechanism.
Here’s their FAQ page: http://www.crohnsmapvaccine.com/faq/
Regardless of this, the rhb-104 trial result was disappointing.
About cipro: anti-map abx combination usually consists of clarithromycin, rifabutin, and clofazimine. Cipro is very rarely used. I for one wouldn’t touch that drug, after reading and experiencing its high toxicity. For me to use it, I must have absolutely no other options. You can read many horror stories about people’s experiences with cipro online. Terrible, seemingly permanent effects.
I agree with you about the reduction of “commensal” gut bacteria (bacterial load) being the possible reason for the anti-map cocktail’s effectiveness. I wrote about it in the HW forum thread I posted above. Let’s not forget also that, antibiotics have actually anti-inflammatory effects independent of their antibacterial effects. Low dose tetracyclines’ anti-inflammatory effect is a well known example. This is also a possible mechanism.
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kiny
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Right. The point is that quinolones like cipro are antibiotics that have shown to be effective in crohn's disease and they are quite effective against E Coli. But quinolones increasingly run into resistance, E coli develop drug resistant mutations.
My worry is that if doctors use clarithromycin, rifabutin, and clofazimine, drugs that are not very effective in treating gram negative bacteria like invasive E coli, they are likely creating resistant E coli and might be impairing more effective treatments like cipro.
If someone has a positive PCR test for MAP (mine were always negative), and you can show that MAP is not an innocent bystander but responsible for the inflammation, then maybe it's justified to use those antibiotics cocktails. But if you don't find MAP, can't prove MAP is causing inflammation, then you will be doing more harm than good by using antibiotics that haven't been shown to be particularly effective in crohn,s disease. And you might create bacteria that become resistant to antibiotics that have shown to be of some success in crohn's disease, like cipro or flagyl.
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Because you are decreasing the number of competitor bacteria in the gut by using those three?
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Kiny
So is the standard of care to stay on een for life ?
And not eat any solid foods ever again in Japan ?
Since your saying they don’t use immunosuppressants /biologics and going off een brings back inflammation
kiny
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Each time you use antibiotics and you don't manage to kill the bacteria, you create a more resistant strains. Antibiotics always come with strong advisory to keep taking the antibiotic as prescribed, stopping too soon will just create resistant strains.
The invasive E Coli found in ileal crohn's disease, AIEC, are highly resistant bacteria (the reside in biofilms, they exploit inflammatory conditions, and they are highly resistant to most antibiotics).
There are few antibiotics effective against AIEC, but cirpo is quite effective, as long as you didn't create prior resistance with other antibiotics. The danger is of course that if you start using anbiotics that target MAP, and the patient actually harbours invasive E Coli (which is very common in CD patients), you will create resistant AIEC strains and mace cipro ineffective.
http://www.medsp.umontreal.ca/IRSPUM_DB/pdf/26755.pdf
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Otakaro Pathways in New Zealand accepts blood samples of crohns patient all around the world. Cultures them, and mostly finds the samples positive. Mine came back positive. The big question is, is MAP the cause, and whether its successful eradication (or something close to that) will result in any improvements in Crohn’s.
kiny
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Immunosuppressants are used, not everyone responds to EN, people who respond best are those with ileal disease, especially those with stenosis.
For adults, EN is far more standard care in Japan than it is in the West. Before biologics EN was also standard care for adults in the West, there are large studies from the 90s where EN was used to induce remission, in adults. Now it's only used primarily in children, which is a shame, because it is an effective way to treat people.
If patient compliance is good, you stay on it as long as you can. There is no reason why anyone needs to go off EN, it has all the nutrients people need.
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I thought the 3 abx cocktail for MAP does not target e.coli, so they can’t create antibiotic-resistant e.coli.
kiny
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E coli resistance to quinolones has increased in the last decades, it is likely due to the indescriminate use of antibiotics, including antibiotics that are not E coli specific.
Using antibiotics against MAP should include the identification of MAP in a biopsy and a positive PCR test. Just testing antibiotics cocktails will likely do more harm than good.
kiny
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Hi, I'm just a crohn's disease patient. When I joined this forum years ago (I was barely an adult back then), I knew nothing about the disease or about the immune system. Reading is a form of therapy for me, a family member is a toxicologist who started to help me with the basics of immunology.
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@kiny, could the immunodeficiency in Crohn’s be secondary, acquired? Only a subset of patients have genetic mutations pointing to immunodeficiencies. Genome-wide association studies for Crohn’s have not shown a meaningful, generalisable evidence for genetic mutations. We might be overlooking the impact of environmental factors, epigenetics. What do you think?
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@kiny Here is a really concise video that explains Qu's approach to treating Crohn's disease - would be interested to hear your views on this....
https://humanpara.org/berkeley-conf...-crohns-disease-by-restoring-innate-immunity/
https://humanpara.org/berkeley-conf...-crohns-disease-by-restoring-innate-immunity/
kiny
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Thanks. They are not very forthcoming about how the medication works. I haven't read anything about site specific stimulation of macrophages. Granulocyte-macrophage colony-stimulating factor has been used, but it's not site specific, but it does seem to correct innate immunodeficiencies.
The underlying premise to correct the innate immune deficiencies and clear the infection is an attractive way to treat crohn's disease because it would lead to sustained improvement and should have far less side effect than stopping inflammation by blocking the adaptive response.
All you really need is a competent macrophage reaction, our immune system is completely capable of shutting down inflammation after an infection subsides, effector cells of the adaptive immune system don't live very long, they die by apoptosis and all that's left is memory cells.
If you correct the innate immune response, a secondary infection would also be cleared more competently since you would have more competent adaptive immune system and more competent memory cells. It should in theory lead to sustained improvement.
The rate of improvement in the graph is what you would expect to see in a sustained but competent immune response that eventually subsides.
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kiny
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It's the adaptive immune system that is developed during life, it adapts. The innate immune system is non-specific and relies primarily on evolutionary factors, it is innate. The innate immune system in the intestine probably evolved together with the microbiome during evolution.
So to answer the question, no I don't think the innate immunodeficiencies are acquired.
There's the hygiene hypothesis, but that also involves the adaptive immune system. The idea that somehow our own immune system lost tolerance to bacteria. I don't believe in it, I think our immune system is competent enough to not mount an inflammatory response against its own flora just for the heck of it at some random date in time. No.
NOD2 mutations in crohn's disease result in loss of function NOD2, a very large portion of CD patients in the West carry the muation. It's seeen in other diseases too like Blau syndrome (people with Blau syndrome have lots of crohn's disease).
There are also defects in autophagy competence (ATG16L1 and IRGM), which again point to innate immunodefficiency.
Vitamin D receptor defects again point to innate immunodeficiency.
Well, crohn's disease is distributed along a Y axis on a map, people in the north have lots of crohn's disease, people in the south much less.
The explanation has been that northern regios have different standards of living, different socio-economic status, and somehow this plays a role. Maybe people from higher economic status freeze their food more, which might result in more foodborne infections.
Another explanation, which could simply tie in to the first explanation, is that people in the North receive less sunlight, and we know vitamin D status affects the innate immune system.
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kiny
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If the question was how relevant the primary immunodeficiency is. Extremely relevant I would say, I don't think there are crohn's disease patients who don't have a primary immunodeficiency.
Crohn's disease patients are consistently shown to have weak immune responses, the adaptive immune system is competent, the innate is incompetent, specifically macrophage competency is hindered by autophagy and signaling protein defficiencies.
(UC doesn't show any of those deficiencies)
Crohn's disease patients are consistently shown to have weak immune responses, the adaptive immune system is competent, the innate is incompetent, specifically macrophage competency is hindered by autophagy and signaling protein defficiencies.
(UC doesn't show any of those deficiencies)
Attachments
Son was tested by Otakaro Pathways, and subsequently became a patient of Prof. Tom Barody (CDD, Sydney), using anti-biotic anti-map therapy. Unfortunately, our son is not one of the success stories, but there are many for whom this treatment does work. Research does back the theory, with the para-physiology of Johnnes in cattle identical to Crohns in humans. Toms "poster" patient is a woman now in her 30's, living a full life in complete remission for years. Kimberly was 17 when she became one of Tom's first patients, when anti-map was in its infancy. She had been told she needed a total colectomy as her lower GI was beyond repair, and she would never have children. A remarkable success story indeed.
I am pleased we partook in the treatment, for though it was unsuccessful for our son, if we had not tried, it would always have been a "what-if" for us. (And I do wonder whether there were other factors involved in his particular lack of success with the treatment, but this is another story all together)
The research into gut bacteria and the implications on our health is being more widely researched now, with strong links to other diseases, including the likes of Parkinsons, Alzheimers and even cardio-vascular implications
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@kiny, Is the immunodeficiency in Crohn’s caused solely by genetic predispositions for all Crohn’s patients?
Also, why do you exclude colonic Crohn’s from your conception of Crohn’s disease?
James C. Lee, Miles Parkes, Genome-wide association studies and Crohn’s disease, Briefings in Functional Genomics, Volume 10, Issue 2, March 2011, Pages 71–76, https://doi.org/10.1093/bfgp/elr009
Also, why do you exclude colonic Crohn’s from your conception of Crohn’s disease?
James C. Lee, Miles Parkes, Genome-wide association studies and Crohn’s disease, Briefings in Functional Genomics, Volume 10, Issue 2, March 2011, Pages 71–76, https://doi.org/10.1093/bfgp/elr009
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Anti-MAP does not seem particularly impressive from what I have read.
For me the really exciting treatment is QBECO which is being developed by Qu Bioligcs. We are talking about the potentially moving from immune suppressing treatments to immune restoring treatments - that is a paradigm shifting change. That's why I am surprised Big Pharma have not taken more notice of QBECO - once its approved there will surely be a significant drop in demand for their expensive immune suppressing treatments of which there are several on the market and more in the research phase as we speak. The whole identify a molecule and block it big pharma extravaganza could be coming to an end!
For me the really exciting treatment is QBECO which is being developed by Qu Bioligcs. We are talking about the potentially moving from immune suppressing treatments to immune restoring treatments - that is a paradigm shifting change. That's why I am surprised Big Pharma have not taken more notice of QBECO - once its approved there will surely be a significant drop in demand for their expensive immune suppressing treatments of which there are several on the market and more in the research phase as we speak. The whole identify a molecule and block it big pharma extravaganza could be coming to an end!
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kiny
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For acute inflammation single treatment infliximab make sense, it manages to stop the inflammatory cascade very quickly. (that's how it was used initially)
(newer immunosuppressant biologics have very low and questionable success rates in inducing acute remission compared to infliximab)
But if you chronically start using it, and you have studies that show that the end result is that patients are not in a better situation than before the therapy. Then some serious questions should be asked if it is truthfully helping patients or if you are simply stimulating long term chronic disease.
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https://ghr.nlm.nih.gov/gene/NOD2#conditions
Yamamoto, S., & Ma, X. (2009). Role of Nod2 in the development of Crohn's disease. Microbes and infection, 11(12), 912–918. doi:10.1016/j.micinf.2009.06.005
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So your argument is that Infliximab should be used as a one off treatment to rescue patients who's inflammation is out of control? I was on Inflix but I am now on Vedo and I feel a lot better in general, and my Crohn's is well under control.
kiny
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Right, that's how it was initially being used. No one had any idea what infliximab would do, TNF-α is an incredibly potent and important cytokine. Blocking such a cytokine was deemed very risky.
Infliximab was only administered once, it induced remissions and then people went back onto maintenance therapy. If the person relapsed a year later, it was used again and again stopped.
It wasn't until some people said it should be used chronically to avoid antibodies that it was used chronically.
Using strong anti-inflammatory for a very short period of time is not new. It is sometimes used when there is an infection to avoid escalating nerf damage. But you don't administer it chronically, because if you do, the infection worsens and people get sicker.
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kiny
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All other biologic immunosuppressant medication is less effective than infliximab, takes longer before people are in remissions, and people relapse faster.
The reasons infliximab is so incredibly effective in inducing acute remissions, is because it acts on the main cytokine that macrophages secrete in the lamina propria of the intestine. The lamina propria is full of macrophages and dendritic cells. There are more immune cells concentrated in your intestine than in any other part of your body.
Macrophages also secrete several interleukin cytokine, but they aren't nearly as important to induce acute inflammation as TNF-α is, blocking other cytokine is not going to be neaerly as effective to induce remission, which is why all those other medications are far less effective, why remissions rates are far lower, to even questionable at times.
The reasons infliximab is so incredibly effective in inducing acute remissions, is because it acts on the main cytokine that macrophages secrete in the lamina propria of the intestine. The lamina propria is full of macrophages and dendritic cells. There are more immune cells concentrated in your intestine than in any other part of your body.
Macrophages also secrete several interleukin cytokine, but they aren't nearly as important to induce acute inflammation as TNF-α is, blocking other cytokine is not going to be neaerly as effective to induce remission, which is why all those other medications are far less effective, why remissions rates are far lower, to even questionable at times.
kiny
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I will put it another way if you like. If inflammation is music, then TNF-α is the director of the orchestra in the intestine. The director can make the band play louder, it can make it play softer. Infliximab acts on the director, newer biologics are far less effective because they act on band members.
A big reason why newer biologics even exist, is due to patents of infliximab that ran out, etc. There is money involved of course. The producer of infliximab its patents have run out, so you now have generic versions of infliximab, which is why the producer of infliximab invented new biologics and tries to claim they are just as effective, but they're not of course, studies show newer biologics are far less effective, because they don't act on the main orchestrator of inflammation, which is TNF-α.
A big reason why newer biologics even exist, is due to patents of infliximab that ran out, etc. There is money involved of course. The producer of infliximab its patents have run out, so you now have generic versions of infliximab, which is why the producer of infliximab invented new biologics and tries to claim they are just as effective, but they're not of course, studies show newer biologics are far less effective, because they don't act on the main orchestrator of inflammation, which is TNF-α.
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Vedo has been great for me. I was not in an acute flare when I started but I did start to feel better from the first infusion and I have so much more energy, sleep better, feel better than I did during my 3 years on inflix...
I agree on the effectiveness for Inflix - I was in hospital and bleeding badly with a flare that was not responding to steroids. They gave me an infusion and with 48-72 hours I was pretty much back to normal. Amazing! I just found it too difficult to live my life on it long term.
I agree on the effectiveness for Inflix - I was in hospital and bleeding badly with a flare that was not responding to steroids. They gave me an infusion and with 48-72 hours I was pretty much back to normal. Amazing! I just found it too difficult to live my life on it long term.
kiny
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That's right, it can shut down inflammation on a dime because it acts on the main orchestrator of inflammation in the intestine, TNF-α. It is incredibly effective in inducing acute remissions.
But if you start chronically blocking this cytokine, you might stimulate chronic disease because you decrease how effective macrphages are in removing bacterial content.
kiny
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Yes. There are probably factors influencing how severe that innate immunodeficiency is though, vitamin D acts on the innate immune system and we know people with vit D defficiency have worse crohn's disease relapses.
Because peyer's patches are found in the small intestine in the ileum, not the colon. And the first signs of active inflammation in crohn's disease is inflamed peyer's patches.
If you start throwing all inflammatory intestinal diseases into one pile, you get lost in the woods trying to make any sense of them.
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The thing I don't understand is - presumably these big pharma companies must look around the research landscape to understand what is coming in the future and to some extent this will inform their activities as they are commercial companies and exist to maximise profit. If I worked for one of these corporations I would look at the coming treatment from Qu BIologics and think ok something is set to come onto the market in the next 5-7 years which could reduce very significantly the demand for our products as well as the drugs we have in pipeline (which are being developed under the same model as current drugs).
Are they just stupid or arrogant or is there some reason I am missing as to why they would want to invest billions into drugs that could well have significantly reduced demand when they come to market? Surely the only answer is to up their game and really push to find a new level of research which is above and beyond the current identify a molecule and block it model. Its the old 'move with the times or get left in the dust' argument.
I think it's fair to say big steps forwards in thinking tend to come from the margins rather than from the centre and Qu are very much outside of the commercialised, share holder value dominated world of the big pharmaceutical corporations. .
kiny
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(I also don't think little kids are coming down with crohn's disease as has been suggested. That's certainly not because I don't appreciate how much those kids and parents are suffering, it is simply because peyer's patches aren't very active during those years, they are active during puberty.
Puberty is still the age where most people come down with ileal crohn's disease. If you have 5-year-old kids who are mysteriously developing inflammation in the intestine, you have to consider the fact that it might be another undefined disease. It certainly doesn't help to categorize every disease that features intestinal granuloma as crohn's disease.)
Puberty is still the age where most people come down with ileal crohn's disease. If you have 5-year-old kids who are mysteriously developing inflammation in the intestine, you have to consider the fact that it might be another undefined disease. It certainly doesn't help to categorize every disease that features intestinal granuloma as crohn's disease.)
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kiny
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As needed through an IV (they're not given orally, antibiotics should ideally always given through IV in CD patients, to spare their intestine, unless there it is a localised antibiotic of course, like rifaximin). I have used many different EN, now it's the stuff from nutricia. It doesn't matter at all what brand you use, EN work because they are highly bioavailable and therefore they limit the fecal stream. All real EN on the market are highly bioavailable, brands don't matter. No I don't eat (real) food.
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kiny
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The biggest issue with EN is not if it works or not, it has clearly been shown that it works in people with ''classical'' ileal disease, especially if there is stenosis or bowel narrowing (it works far less well in non-classical disease if there is colonic involvement). The biggest issue is patient compliance, the stigma of running with a tube, the stigma of never being able to eat with others, the fact you need to be monitored for calorie defficiency. That stigma and the care needed to avoid nutritional defficiency, probably limits the adoption, but that stigma doesn't need to be there, as Japan has shown, where EN is standard care for adults.
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Aren’t you worried about vegetable oils, and laboratory impurities (and heavy metals, allergens) of the substances in the products? You are ingesting them every day.
Which of these are you currently using: https://www.nutricia.com/en/advanced-medical-nutrition/products.html
About antibiotics, could you elaborate on “sparing the intestines”? What happens to the intestines when you take the abx orally?
Also, you mentioned tube, do you not take the EN orally?
Which of these are you currently using: https://www.nutricia.com/en/advanced-medical-nutrition/products.html
About antibiotics, could you elaborate on “sparing the intestines”? What happens to the intestines when you take the abx orally?
Also, you mentioned tube, do you not take the EN orally?
kiny
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I doubt it.
In classical ileal disease, immune responses to the fecal stream are most likely coming from peyer's patches. The colon doesn't have them, if there is patchy inflammation in the colon it's probably more related to simple bacterial load in the colon instead of bacterial load from the fecal stream.
kiny
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You just want to kill the bacteria that have entered the lamina propria, the wall of the intestine. Antibiotics are broad spectrum, you don't want to indescriminately kill all the bacteria in your intestine, that's why bacteriophage therapy is so interesting, it's specificity. I have to go now, nice talking to you.
Studies show efficacy for enteral nutrition, but unfortunately the relapse rate remains high compare to the effort it takes to follow it...
https://www.ncbi.nlm.nih.gov/m/pubmed/30098021/
https://www.ncbi.nlm.nih.gov/m/pubmed/30098021/
kiny
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He has been writing about crohn's disease for decades. He did studies on EN in the 80s, and was one of the first people who realized it was effective.
If you want to read interesting paper, looking through his papers is a good start. He is also one of the first people who realized crohn,s disease was an innate immunodefficiency.
https://www.bmj.com/content/288/6434/1859.abstract
The same work he did in London was supported by other studies in London about the EN in the 80s, they knew the antigen causing inflammation in crohn's disease was bacterial, and they knew it was in large part from high bacterial load of the fecal stream.
They were one of the few researches who correctly identified that it was bacteria entering the epithelium and lamina propria, acitving the peyer's patches and immune system in crohn's disease 35 years ago.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1432937/pdf/gut00383-0014.pdf
1985
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kiny
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In 1986 these same people from London realised that the immune response in Crohn's disease is very different from that seen in UC.
https://www.ncbi.nlm.nih.gov/pubmed/3732890
The present findings show that the acute phase response differs significantly between Crohn's disease and ulcerative colitis.
These same people in London then realised that macrophages in crohn's disease have issues clearning crohn's associated invasive E Coli.
https://www.ncbi.nlm.nih.gov/pubmed/25809337
If crohn's disease is one day cured, these people should get a nobel price. The have written some of the most important papers on crohn's disease.
https://www.ncbi.nlm.nih.gov/pubmed/3732890
The present findings show that the acute phase response differs significantly between Crohn's disease and ulcerative colitis.
These same people in London then realised that macrophages in crohn's disease have issues clearning crohn's associated invasive E Coli.
https://www.ncbi.nlm.nih.gov/pubmed/25809337
If crohn's disease is one day cured, these people should get a nobel price. The have written some of the most important papers on crohn's disease.
kiny
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Segal is also responsible for the study where they first started checking innate immunocompetence in crohn's disease.
The irony is that the most interesting studies about crohn's disease are also the easiest to understand.
How do you test if someone is immunocompetent? Well, you check how they deal with infections.
What they did was inject heat killed E Coli into the forearm of healthy people, people with UC, and people with crohn's disease.
What you find is that people with crohn's disease do not have a competent acute inflammatory reaction, magrophage reaction and neutrophil recruitment is stunted.
The study is on the forum somewhere in full, I posted it in 2013, it's copyrighted but it's still there in full if you care to look for it, it was featured in The Lancet.
The irony is that the most interesting studies about crohn's disease are also the easiest to understand.
How do you test if someone is immunocompetent? Well, you check how they deal with infections.
What they did was inject heat killed E Coli into the forearm of healthy people, people with UC, and people with crohn's disease.
What you find is that people with crohn's disease do not have a competent acute inflammatory reaction, magrophage reaction and neutrophil recruitment is stunted.
The study is on the forum somewhere in full, I posted it in 2013, it's copyrighted but it's still there in full if you care to look for it, it was featured in The Lancet.
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I've followed their work since the first patients were treated - it gives me hope.
kiny
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GM-CSF, granulocyte-macrophage colony-stimulating factor, was the only real trial so far to boost the innate immune system in crohn's disease. With 15 patients, 12 improved significantly, 8 went into remission.
I don't know what happened after that, Segal (he wasn't involved in the study but he mentions the study in his papers) said it wasn't FDA approved, I don't know what happend with the treatment, I would have to ask people involved in the study.
I don't know what happened after that, Segal (he wasn't involved in the study but he mentions the study in his papers) said it wasn't FDA approved, I don't know what happend with the treatment, I would have to ask people involved in the study.
kiny
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Ah, they did keep trying GM-CSF after that first trial. It was developed as Leukine with brand name Sargramostim. Two trials I can find, it failed in adults, one was successful in kids. The adult trials were done in Japan and Canada. The low success rate in adults was probably why it was never FDA approved.
kiny
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It's also interesting that if you read Segal his studies, he shows that crohn's disease patients not only have a competent adaptive response, they also have competent neutrophils. The reason there isn't a competent neutrophil reaction is just because of lack of macrophage cytokine release. There are not nearly enough neutrophils recruited to have a competent reaction in the intestine. But neutrophils themselves are completely competent in CD.
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If I remember right, this was the first study which pointed out to immunodeficiency in Crohn’s patients: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(76)91024-2/fulltext
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Well, these type of treatments basically accomplish what I would expect given the nature of the disease. Temporary relief.
What is interesting to me is that the authors go out on a speculative limb, without any evidence at all, and indicate that improper use or compliance using the drug may be the underlying reason. I will also speculate that not angering the large drug companies for the failure is the actual reason for that statement.
Since that would require virtually all the study participants to be misusing or underutilizing the treatment that would seem very unlikely.
I think Kiny’s thoughts on this far more likely although I have different thoughts on the nature of the disease cause in some respects.
I am more interested on Kiny’s treatment if it has improved her condition as it is real life and not subject to a financial interest. Possibly she could start a thread on it.
Best regards.
Dan
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Judging by kiny’s way of thinking, interacting, arguing, writing and interests, I would be surprised if kiny turned out to be a woman.
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Man or woman, he or she (I think she is a woman) has an unusually logical thought process. That is why I am always interested in what she has to say.
Her treatment would reflect this and that piques my interest.
I am always interested in another angle of attack on this disease.
Although I am in my seventh year from experiencing the disease, I never want to struggle with it again and I will spend time making sure that it does not occur again.
Dan
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I agree. That’s also why I am asking him questions. I am sick of living with Crohn’s.
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@kiny thanks for sharing your knowledge first of all
I have 2 questions
1. I'm also curious about reumatism and type 1 diabetes, I heard somehow they're related to crohn's disease, are they also immunodefeciency state?
2. if crohn's disease is immunodeficiency state, why some others organ other than intestine aren't infected?
I have 2 questions
1. I'm also curious about reumatism and type 1 diabetes, I heard somehow they're related to crohn's disease, are they also immunodefeciency state?
2. if crohn's disease is immunodeficiency state, why some others organ other than intestine aren't infected?
kiny
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Hi, people with Crohn's disease have aphthous ulcers in their mouths, just like other diseases with impaired innate immunity like Chronic granulomatous disease.
Aphthous ulcers in UC are extremely rare compared to crohn's disease, most people don't have them. UC doesn't have impaired innate immunity.
Why the intestine in crohn's disease and not some other organ...because crohn's disease is impaired immunity of macropahages...the large large majority of macrophages are in the intestine. The ileum is rich in peyer's patches.
Other organs besides the intestine ARE affected by Crohn's, sometimes seriously so. It's the whole "extra-intestinal manifestations" thing. Usually it is the joints that are also affected. In my case it was pericarditis. Several years after diagnosis my Crohn's inflammation also popped up in my pericardium - the membrane surrounding the heart. I ended up getting open-chest surgery to remove the inflamed pericardium. That's why I gave in and went on biologics. I didn't want to go through another episode like that. And so far, one and half years later, the Stelara is working pretty well. There have been no further extra-intestinal episodes and the intestinal Crohn's is in complete remission.
kiny
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Macrophages their life generally consists of waiting within tissue. They hide in the most strategic places where a bacteria might enter.
When a doctor does a white blood cell count, they are not measuring macrophages, they are measuring monocytes from the blood, they will eventually evolve into tissue macrophages.
Macrophes in the intestine are strategically hiding in the lamina propria, it is the tissue right behind the epithelium of the intestine, they hide behind M cells, they hide near peyer's patches, they hide in places where bacteria keep causing trouble. They are are your first line of defense when a bacteria enters your intestine. Once they encountered a bacteria, they sound the alarm, they do this by releasing cytokine, one of them is TNF-α, which is the main orchestrator of fever and inflammation.
Macrophages in crohn's disease have issues in that specific acute response, the macrophages are impaired, they don't react appropriately, the acute phase is stunted because of it. As a result the adaptive immune system is chronically activated to compensate.
When a doctor does a white blood cell count, they are not measuring macrophages, they are measuring monocytes from the blood, they will eventually evolve into tissue macrophages.
Macrophes in the intestine are strategically hiding in the lamina propria, it is the tissue right behind the epithelium of the intestine, they hide behind M cells, they hide near peyer's patches, they hide in places where bacteria keep causing trouble. They are are your first line of defense when a bacteria enters your intestine. Once they encountered a bacteria, they sound the alarm, they do this by releasing cytokine, one of them is TNF-α, which is the main orchestrator of fever and inflammation.
Macrophages in crohn's disease have issues in that specific acute response, the macrophages are impaired, they don't react appropriately, the acute phase is stunted because of it. As a result the adaptive immune system is chronically activated to compensate.
http://jem.rupress.org/content/206/9/1839
this macrophage theory seems to have been already discussed in some studies.
Now, could they find a cure easier if this is right?
this macrophage theory seems to have been already discussed in some studies.
Now, could they find a cure easier if this is right?
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http://jem.rupress.org/content/206/9/1839
this macrophage theory seems to have been already discussed in some studies.
Now, could they find a cure easier if this is right?
I posted some of the relevant papers on immunodeficiency in the anti-map therapy support group, if anyone is interested.
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kiny
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All the serious side effects they saw in patients was on combination therapy, once they removed the azathioprine and realized that combo therapy wasn't needed to make infliximab effective, but they instead could regulate the dosage of infliximab, there were considerably less serious side effects. The serious side effects were clearly being caused by the addition of azathioprine, it is good that they stopped combo therapy, it is never needed when infliximab dosage can be modified.
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My question was more in regards to its use as a monotherapy, on its own. I am also wondering your opinion on using rapamycin for Crohn’s.
Gut. 2008 Sep;57(9):1294-6. doi: 10.1136/gut.2008.157297.
Use of sirolimus (rapamycin) to treat refractory Crohn's disease.
Massey DC1, Bredin F, Parkes M.
Author information
Abstract
We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn's disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn's disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn's disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn's disease symptoms with the Harvey-Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn's disease.
PMID: 18719139 DOI: 10.1136/gut.2008.157297
https://www.ncbi.nlm.nih.gov/pubmed/18719139
Mohamed Mutalib, Osvaldo Borrelli, Sarah Blackstock, Fevronia Kiparissi, Mamoun Elawad, Neil Shah, Keith Lindley, The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children, Journal of Crohn's and Colitis, Volume 8, Issue 12, 1 December 2014, Pages 1730–1734, https://doi.org/10.1016/j.crohns.2014.08.014
https://clinicaltrials.gov/ct2/show/NCT02675153
Gut. 2008 Sep;57(9):1294-6. doi: 10.1136/gut.2008.157297.
Use of sirolimus (rapamycin) to treat refractory Crohn's disease.
Massey DC1, Bredin F, Parkes M.
Author information
Abstract
We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn's disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn's disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn's disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn's disease symptoms with the Harvey-Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn's disease.
PMID: 18719139 DOI: 10.1136/gut.2008.157297
https://www.ncbi.nlm.nih.gov/pubmed/18719139
Mohamed Mutalib, Osvaldo Borrelli, Sarah Blackstock, Fevronia Kiparissi, Mamoun Elawad, Neil Shah, Keith Lindley, The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children, Journal of Crohn's and Colitis, Volume 8, Issue 12, 1 December 2014, Pages 1730–1734, https://doi.org/10.1016/j.crohns.2014.08.014
https://clinicaltrials.gov/ct2/show/NCT02675153
kiny
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I don't know what rapamycin is. Regarding azathioprine, I don't think there is much of a future for it when you now have biologics. If you're going to use immunosuppressant, you might as well use one that is highly effective like infliximab and is at least as safe, if not safer than the less effective treatment.
I don't agree with how infliximab is used chronically, I think we should go back to using it only during acute phases of inflammation (even with the risk of antibody development). Giving it chronically is clearly not the way forward if you look at that depressing study.
But infliximab will always remain the most effective of all the biologics to treat acute inflammation, since TNF-α is the cytokine behind the inflammatory escalation.
I don't agree with how infliximab is used chronically, I think we should go back to using it only during acute phases of inflammation (even with the risk of antibody development). Giving it chronically is clearly not the way forward if you look at that depressing study.
But infliximab will always remain the most effective of all the biologics to treat acute inflammation, since TNF-α is the cytokine behind the inflammatory escalation.
