Current and future aspects of IBD research and treatment: The 2022 perspective

[asadmom]

"Inflammatory bowel diseases (IBD) have seen major progress in current concepts and treatment regimes. Based on the theory of an inadequate “overshoot” of the mucosal immune response to the intestinal microbiome, therapies have been developed to interfere with the key mediators of inflammation from cytokines, including TNF and IL12/23, to integrins such as α4ß7 and intracellular cytokine signal transducers such as janus kinases. Recently, sphingosine-1-receptor agonists were marketed to suppress mucosal inflammation by sequestering lymphocytes in peripheral lymph nodes. However, the aim of these regimes targeting immunity to induce a long-term deep remission, including mucosal healing, is missed in most patients. Contrasting these anti-inflammatory mechanisms of action, the pathogenic focus has finally shifted to the mucosal antibacterial barrier in both Crohn´s disease and ulcerative colitis."


https://www.frontiersin.org/articles/10.3389/fgstr.2022.914371/full#B59

 

[asadmom]

"...achieving steroid-free “deep remission,” including MH, with infliximab in combination with an immunosuppressant did not prevent progression"

MH =mucosal healing

"This should motivate us to rethink the therapeutic approach focusing on the novel pathogenetic concepts derived from extensive genetic and microbiological studies and, above all, understanding IBD as a barrier disease"

Barrier disease?

 

[Pangolin]

I think that defining remission--even "deep" remission--is a huge problem for many of these studies, and that's what may have been going on in some of those infliximab studies. The thing is, mucosal healing is only part of the picture--in particular, there's also transmural healing. It's also worth considering histological remission and biochemical remission as well as symptomatic remission.

Anyway, if you don't get both mucosal healing and transmural healing (full thickness healing, bowel wall thickness normalization), I don't think you have deep remission. I have seen one study in which people who achieved stable deep remission (including transmural) for some time on infliximab didn't relapse when they stopped infliximab. Studies such as that have led me to believe that the author is correct re Crohn's as a barrier disease (some sort of damage to the intestinal lining), and that if you really do get full and complete healing of the barrier then maybe you have essentially been cured.

Hopefully we'll get more studies eventually of what happens long-term with people who have great results from the il-23 drugs (including Stelara), because some early indications are that that remission can be durable.

 

[asadmom]

I think that defining remission--even "deep" remission--is a huge problem for many of these studies, and that's what may have been going on in some of those infliximab studies. The thing is, mucosal healing is only part of the picture--in particular, there's also transmural healing. It's also worth considering histological remission and biochemical remission as well as symptomatic remission.

Anyway, if you don't get both mucosal healing and transmural healing (full thickness healing, bowel wall thickness normalization), I don't think you have deep remission. I have seen one study in which people who achieved stable deep remission (including transmural) for some time on infliximab didn't relapse when they stopped infliximab. Studies such as that have led me to believe that the author is correct re Crohn's as a barrier disease (some sort of damage to the intestinal lining), and that if you really do get full and complete healing of the barrier then maybe you have essentially been cured.

Hopefully we'll get more studies eventually of what happens long-term with people who have great results from the il-23 drugs (including Stelara), because some early indications are that that remission can be durable.

So perhaps once you get to the true deep remission, the disease pathway is altered hence cured for some patients?

 

[Scipio]

So perhaps once you get to the true deep remission, the disease pathway is altered hence cured for some patients?

"Cured?" One can hope, but the only docs I've ever heard use the word "cure" in the same breath with Crohn's disease are quacks peddling miracle mystery medicine and fad diet books.

Modern medicine has made a lot progress in treating Crohn's, but about the closest to "cure" you will ever a legit medical scientist say is maybe "durable remission." And even that tends to be stated more aspirationally than as a claim of promised results.

 

[asadmom]

"Cured?" One can hope, but the only docs I've ever heard use the word "cure" in the same breath with Crohn's disease are quacks peddling miracle mystery medicine and fad diet books.

Modern medicine has made a lot progress in treating Crohn's, but about the closest to "cure" you will ever a legit medical scientist say is maybe "durable remission." And even that tends to be stated more aspirationally than as a claim of promised results.

Say if you live like a non-IBD person with no medication intervention, is it reasonable to say that you have no Crohn's = you are cured?

How do we ever know if a person has Crohn's if that person exhibits no traits of Crohn's?

 

[kiny]

No reason why Crohn's Disease wouldn't be curable.

Intestinal TB, a disease that most closely mimics Crohn's Disease, was incurable for centuries. We discovered Streptomycine, we could sudenly kill mycobacterium tuberculosis, and we could cure people.

Pasteur invented pasteurization and intestinal TB was wiped off the Western continent. That same world famous Institut Pasteur is currently researching crohn's disease.

 

[Jbungie]

Kiny, love your knowledge and insight! Are you a doctor of some sort? You seem to have in depth knowledge, so just curious!

 

[Scipio]

Say if you live like a non-IBD person with no medication intervention, is it reasonable to say that you have no Crohn's = you are cured?

How do we ever know if a person has Crohn's if that person exhibits no traits of Crohn's?

We know for sure when they fall out of remission and suffer a flare. Until then we a have a remission that we hope is very durable.

Several long-term studies of relapse rates among patients in solid remission who discontinue biologics (but often they continue taking immunomodulators rather than risk going totally pharmaceutically naked). Perhaps the most famous of these was the STORI trial. The STORI study was a prospective, observational study of 115 patients with Crohn’s disease on combination therapy (infliximab + immunomodulator) for at least 1 year who discontinued anti-TNF after being in steroid-free clinical remission for at least 6 months. The relapse rates at 12 and 24 months were 43.9% ± 5.0% and 52.2% ± 5.2%, respectively, with a median time to relapse of 16.4 months. The long-term follow-up (median 7 years) showed that only in approximately 20% of patients, remission was kept without development of major complications or without the need to restart infliximab or another biologic.

The trend observed so far in all these studies is that if you wait long enough pretty much all the Crohn's patients who discontinue medication will eventually relapse.

 

[Pangolin]

There is hope of durable remission if patients can reach the right targets, and the knowledge about what the right targets are is improving. I can't find the old study right now, but there was a promising one in which all of the patients who were on infliximab who had both mucosal healing and transmural healing and who then stopped infliximab had no relapse for a year followup.

Unfortunately I don't think infliximab is very good at getting patients to reach those targets.

Anyway here are a few relevant papers. The barrier healing one is particularly interesting.

Mucosal healing does not predict continued remission after infliximab discontinuation: https://pubmed.ncbi.nlm.nih.gov/25330148/

Transmural healing more useful than mucosal healing: https://onlinelibrary.wiley.com/doi/abs/10.1111/apt.16232

Transmural healing as independent predictor of outcomes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193655/

Barrier healing predicts adverse outcomes: https://www.gastrojournal.org/article/S0016-5085(22)01192-1/fulltext

 

[asadmom]

No reason why Crohn's Disease wouldn't be curable.

Intestinal TB, a disease that most closely mimics Crohn's Disease, was incurable for centuries. We discovered Streptomycine, we could sudenly kill mycobacterium tuberculosis, and we could cure people.

Pasteur invented pasteurization and intestinal TB was wiped off the Western continent. That same world famous Institut Pasteur is currently researching crohn's disease.

View attachment 4405

I can't find literature about their research efforts that is more recent. Do you know how they are doing there?

 

[kiny]

I can't find literature about their research efforts that is more recent. Do you know how they are doing there?

There is a cluster of groups in France focused on pathogens involved in crohn's disease.

If you look at the list of research I compiled on AIEC, you'll see most of these studies are from France.

https://crohnsforum.com/threads/aiec-index.52198/

One of the people that set this research in motion is called Arlette Darfeuille-Michaud. If you search through my list, you'll see her name in most of the studies. She is no longer around sadly.

She did research on Klebsiella and E Coli. In 1998 she noticed that the ileum of people with crohn's disease were colonized with pathogenic E Coli. She discovered AIEC.

There were lots of PhD students studying under her guidance. In 1994 she created a lab. That lab is called "lab M2iSH" in central France (Microbes Intestin Inflammation et Susceptibilité de l'Hôte). The lab is linked to the University close by, and is financially sponsored by the research wing of the EU. There are also companies involved with the lab, the companies trying to get bacteriophages to market, French food companies that can help with dietary interventions in crohn, etc.

Institut Pasteur is also now involved in this research, they have capabilities that a smaller lab like M2iSH can not fulfill. The bioistatistics team at Pasteur has tons of computational power and people who know how to do all the mathematical modeling to discover all the bacteria and genes involved in crohn's disease. You can also find all their studies, often working together with M2iSH.

https://www.sciencedirect.com/science/article/abs/pii/S1471490603003259
https://academic.oup.com/ecco-jcc/article/11/7/840/2895107
https://gut.bmj.com/content/66/6/1039

 

[asadmom]

Do you know if there is any more recent update? I imagine this is a very tough endeavor. Would be great to know what is going well and what is not.

I overheard that the anti-map vaccine trial is gonna release their results in a few months. Not holding breath but nevertheless we can know definitively if the map theory holds water.

 

[kiny]

I got into contact with a local vet lab with a lot of experience doing Ptb tests on ruminants, did an IS900 blood PCR test for MAP, and a few months of culture, both were negative.

For most herds, only the stool is tested. There's no need to do a blood test, if a ruminant has Ptb, it is in the stool. Some labs have government contracts to map the spread in the farming industry or in wild animals, and they do blood tests.

If MAP is involved, it is really hard to reconcile the idea that people in urban areas are more likely to develop crohn's disease than those in rural areas. The antibiotics that have an effect in crohn's disease like fluoroquinolones, likely target enterobacteriaceae like E coli, Klebsiella, Salmonella, etc. Even though cipro is macrophage penetrating, I really doubt it is targeting MAP.

 

[kiny]

Cipro could also simply act by bringing down bacterial load, but it likely acts in tissue. How cipro brings down inflammation in crohn's disease is unclear, but the fact quinolones penetrate phagocytes and seem more effective than antibiotics that don't, tells me these antibiotics act on activated macrophages and target enterobacteriaceae that have penetrated phagocytes in tissue. If quinolones worked by simply lowering bacterial load in the lumen, most antibiotics should work for crohn's disease, and they clearly don't. Cipro is able to bring down inflammation in crohn's disease, many other antibiotics are not.