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Leonard Weinstock, MD - Inflammatory Bowel Disease II (2017 Conference) (LDN, low dose naltrexone)
Inflammatory bowel disease is a condition that we see as gastroenterologists on a daily basis. I'm Dr. Weinstock. I'd like to review inflammatory bowel disease, what the traditional approaches are, and some of the newer changes that we've seen with low dose naltrexone. Here are my disclosures.
A complex conglomeration of things go on to trigger the onset of inflammatory bowel disease. Virtually everybody is thought to have a predisposing genetic makeup to be able to get chronic inflammatory bowel disease, and more and more genetic tests have been done to come up with genetic markers that show who's likely to get one disease versus another. But what happens is we're exposed to bacterial antigens and because of our risk genes, perhaps triggered in addition by the environment - which could be stress, it could be an acute infection - we start to misregulate and misdiagnose a bad bacteria as being even worse, which then sets up an immune response, which then becomes chronic and leads to the inner circle, IBD, or inflammatory bowel disease. So poor recognition of what actually could be a good bacteria, through a series of events, can keep this condition going and going and going.
This is a cartoon that I made up showing the mucosa, bacteria in green, the mucus layer that's created by goblet cells in yellow. You have the enterochromaffin cells, which make certain triggering proteins that may bring up inflammatory cells. And we see a few inflammatory cells in the little stars, two little stars in these linings. And then down deeper, we have a vein in blue and an artery in red, and these are of course of capillary size. And on the lower left we see a healthy colon. So if everything's in good status or making mucus to keep the bacteria away from the lining to some degree, or at least protect the goblet cells; and the links between the cells, the zonulin and occludin, which tighten up the junctions between each cell, are working, everybody's happy. Everything's fine. We don't have excess cells in the submucosa, down below the lining.
But with slide 5, we see the effect of dysbiosis. When I first started off, I was talking about abnormal bacteria or poor recognition of bacteria, and then these organisms invade. With the abnormal mucus layer, the brown bacteria start to invade, go into the crypts of the mucosa. We see some damage to the lining cells, the zonulin and occludin become damaged, so the tight junctions become weak and we get a leaky gut. And then the paneth cells start drawing in inflammatory cells, which are in the stars. And then we have leaky vessels as well, increased vascular permeability, the blue and the red orange bars below. And then what comes from this is an inflamed colon with thickening, loss of vascularity, pus on the top and ulceration on the left. So that's an example of Crohn's colitis.
Slide 6 shows this in more elegant cartoon form. The gut microbiome is disrupted. We go through a challenge-disrupted epithelial barrier. These grab onto the antigens, which activates T-cells, which are really important when it comes to thinking about the use of low dose naltrexone (LDN). T-cells can secrete inflammatory cytokines, especially TNF-α, and along the way we start bringing in other T-cells, which have memory and stay around forever. And these two cells constantly secrete TNF-α which damages the tissue lining, which disrupts the epithelial barrier, which allows more bacteria to get through, and we have the vicious cycle. And in the blood vessels that are nearby, there's increased permeability, as I showed in the cartoon. And we have places for the inflammatory cells to get out and keep the activity going.
Slide 7. This is the pre-disease state and the triggers that result in barrier dysfunction and allow for their bacterial translocation. Again, what are the genetic factors involved? If these are abnormal because you're born with the wrong genes, then you can't protect yourself against the bacteria. You can't handle them well. You have excess amounts of cytokines being produced, causing damage to the gut lining. There's a variety of environmental factors that a person can go through: if they're taking anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, these can break up the gut lining; excess smoking factors in as well.
In Phase 2, that's when things start to get inflamed and the bacteria starts going in. There are these receptors, the toll receptors, that allow translocation of bacteria, which are increased in Crohn's disease and, and important as treatment option for low dose naltrexone. The immune activation that keeps on going with the T-cells, again is an important role for LDN. We lose regulatory T-cells, and LDN has been shown to play a role in improving T-cell regulation. Then the active T-cells that damage the lining by TNF-α also affect cells that can be affected in a positive way by LDN.
As the disease goes on, we have these deep ulcers that develop, and Crohn's fibrosis, which leads to scar tissue and narrowing. Or the ulcer goes down all the way through, and bacteria come with it and create an abscess or fistula tract. Chronic inflammation can be a factor a little bit more for ulcerative colitis than Crohn's disease, and that increases the risk for cancer. And then there are extra intestinal manifestations that may well be due to autoimmune triggers with both diseases.
So, the idea for doctors is to help the individual with inflammatory bowel disease with medication, and also to give some dietary advice. We want to suppress inflammation in general. We want to alter the functions and abilities of these white cells, particularly the lymphocytes. There are these chemicals called prostaglandins and free radicals that we want to bind, to decrease the damage done to the lining cells, which keep the vicious cycle going. We can alter the microbiome and improve immunity, as shown below, with antibiotics, probiotics, diet, immunoglobulins that are oral and possibly even FMT, fecal microbiota transfer. The role of an LDN in this is to improve the DNA regulation of immunity, improve those T regulatory cells, reduce inflammation by means of endorphins reducing T- and B-cell activity. And also LDN, as naltrexone can improve vascular integrity and tighten up those junctions.
This is a tough disease to treat and the things that we use to treat it are risky. Mortality was known to increase with prednisone, narcotic use, and age. Interestingly, narcotic use is associated with this, and what we give our patients with LDN of course, is antinarcotic. So that's an interesting dichotomy to think about and theorize. Infections are increased in patients with that inflammatory bowel disease because of the medications they get, in particular prednisone, and in this particular study, infliximab. But it goes true for the other biological agents.
Prednisone. So many side effects, that you see listed on the right. Main mechanism of action, MOA: it is a general treatment. It suppresses white blood cell activity. It improves vascular permeability. It suppresses those arachidonic acids that damage the lining cells and decreases IL-6. But there are so many problems of using it. Just trying to protect yourself by taking calcium and vitamin D is not necessarily the answer. There are some new alternative forms of the steroids, which decrease absorbency; and once the absorption occurs, it goes to the liver where it is destroyed before it circulates to affect the rest of the body.
5-ASA. There is sulfasalazine, mesalamine, for example. These are drugs that work mainly on the mucosal side, so they're best for ulcerative colitis. They inhibit leukotrienes 5-lipoxygenase. They're free radical scavengers, and basically block the bad effects of the white blood cells. Generally, they're well tolerated. Occasionally there's a diarrheal reaction, 3% hair loss, and 2-3% headache; and hypersensitivity conditions, which are more along the lines of allergies, are factors. But they're first line, good drugs in ulcerative colitis.
Thiopurines are a step-up drug. They've not been shown to induce a remission, but they can help keep somebody in remission. But there are a number of side effects, on the right: 3 - 7% have allergic pancreatitis. The white blood can count can go down because the bone marrow can be suppressed. It could be liver disease, infections, lymphomas, and skin cancers; these are major concerns about using these long term.
The anti-TNF infliximab, uh, the anti TNF infliximab and adalimumab for example, are drugs that bind that TNF that the lymphocyte secretes. When it binds it, it takes it out of circulation and by doing so, many of the symptoms of inflammatory bowel disease, ulcerative colitis and Crohn's disease can be controlled. The problem is they are foreign body in themselves, and our body can react against them and cause inactivity. They can also trigger antibodies, causing lupus, arthritis, psoriasis; and to a lesser degree the thiopurines can be responsible for lymphoma.
Here's just an example of this expensive drug <infliximab> that basically costs approximately $20,000 to $40,000 a year to treat somebody with Crohn's disease. So, this is looking at the Crohn's disease activity index. Compared to placebo, there's a 20% gain, but with a very high dose. With just the standard dose we have a 14% gain over placebo, showing that we're spending a lot of money treating patients with Crohn's disease, many who do not respond to a very commonly used drug.
There is a new drug that came out two years ago, an anti-integrin. That’s vedolizumab, that basically makes the lining of the blood vessels less leaky, so the white blood cells, the lymphocytes can't get out and go to the lining of the intestine to make it more inflamed. In general, they're safer, but they take longer to work because you need to treat the active inflammation present. Here's an example of how well it works. This is in Crohn's disease, where there's a 14% improvement; and in terms remission, 17% delta, or 39% of the patients on vedolizumab went into remission.
And now the latest drug for Crohn's disease is ustekinumab, that's given intravenously. With this antibody we see, in general, some increased risk of infection and skin malignancy, but not to a great deal. And it is fairly effective in Crohn's disease, especially those patients who are right off the bat, they never took anti-TNF. They are on the right side, TNF naive, and had a very good response, nearly 30% improvement over placebo to try to get it into remission.
Herbs have been used in ulcerative colitis, and there've been a number of controlled studies supporting one over the other. But it's been something relatively elusive, in that the degree of response is relatively mild.
Probiotics have not been very helpful in Crohn's, more in ulcerative colitis. Usually they're well tolerated. Occasionally they can lead to bloating and GI symptoms. There is virtually no risk for infection unless somebody is truly immunocompromised.
Anti-inflammatory diets are something that I do recommend, often starting with a gluten free diet. If the patient's very active in their health and are willing to do anything, then I'll recommend a specific carbohydrate diet.
Vitamin D is something that I use regularly, especially with steroids, but also as an anti-inflammatory drug.
As a complement to therapy to deal with persistent diarrhea, I give immunoglobulins by mouth; derived from a cow, and purified. It's been used for over 25 years in the veterinary world, and then it's been used since 2013 for enteropathy of all types in man. It's a medical food, serum bovine immunoglobulin. It binds the bacteria, so it gives the chance for the leaky gut to resolve on its own.
Here's a little chart showing how it works to break the vicious cycle and bind the microbiome. They're acting right on the lining so the gut can improve the immune status, improve the gut barrier, and improve nutrient absorption.
What about low dose naltrexone? Along the way I've given you ideas on why inflammatory bowel disease patients get into trouble. I think the things that are important are highlighted in yellow. It regulates cell growth, so it has the chance of reducing T- and B- cell activity, in particular T-cell with inflammatory bowel disease. It reduces inflammation in general. It decreases permeability. It decreases cytokine from activated cells, so the IL-6, the TNF-α, can be reduced and that can help. And then it shifts the immune status from a TH2 to TH1 status, which is a generally less inflammatory process. As we get activated receptors with the LDN, more endorphins are released, and that decreases the T- and B-cell activity, and lessens permeability.
The toll receptors I think are important in reducing bacterial translocation, and stabilizing. This receptor decreases the activity and plays a role as well.
Methionine enkephalin (MENK) is an offshoot of low dose naltrexone. When it binds to these regulatory cells, the T-cells, it suppresses immune activity, which balances things out: going back to one of my first slides with Venn diagrams, we have too much activity going on because of genetic phenomenon, and by poor recognition of our own bacteria, that drives the system forward.
This slide goes over a list of the studies that have been done. There are 3 open label studies, and 2 double blind studies, performed and reported in literature. We'll just dip into this a little bit. Looking at the randomized controlled studies, and this was looking at LDN as adjunctive therapy in adults, so they could maintain their other therapy, which was only partly efficacious. Adding LDN 4.5 mg to 18 patients resulted in a significant drop in Crohn's disease activity, index scores versus controls, with a 48% delta between the active therapy and controls. And then it looked at whether it really did make a difference in the endoscopy, because may times in Crohn's patients, they feel better, but they don't actually look better inside. But there was a dramatic improvement in patients’ scores: 33% went into complete remission versus 8% of controls.
Dr. Smith also looked at LDN as the only therapy in children dosed at a 0.1 mg/kg, versus placebo. They started out with an activity index at 34, and after just eight weeks it dropped to 22, which was clinically significant; and 25% went into remission. And there were no serious adverse events. Treating for eight weeks is a short period of time, so seeing a clinically and statistically significant improvement is really remarkable.
My own experience in Crohn's disease is that in 33 patients who were moderate to severe, who were failing therapy, I gave treatment over a prolonged period of time of 40 weeks. I did have some withdraw because of side effects, usually insomnia. I found that there was a good response in half the patients, 15 out of 33 had a positive response. Of these 15 patients, 11 had colonoscopy before and after treatment, and 8 of the 11 had complete endoscopic improvement, which is really remarkable.
Here's an example of a patient who lost their colon to Crohn's disease. She had activation 4 years after surgery. She was failing infliximab and her symptoms were diarrhea and fatigue. On the lower left, we see the ulcer that was present in the ileum. I added LDN and she went into clinical and endoscopic remission in 2 months. As you can see here, with the scar being a little bit higher up on the image, basically that was the area where the ulcer was. She has been in remission for 6 years now. She actually is on infliximab and LDN, and the combination effect is adequate to keep her in a good state of affairs.
Here is a patient on whom I did colorectal cancer screening. I inserted the scope into the ilium, and he had ulcers that looked like Crohn’s disease. Because the patient had significant multiple sclerosis, despite the fact that his ileum was normal, I offered low dose naltrexone and he initially found benefit in the MS symptoms. A year later, he still was finding benefit. He could actually walk without the 2 canes he required previously, and the ileal ulcers, as we see, are all normalized, all healed.
This is a patient with ulcerative colitis who was failing Remicade. His symptoms were so severe he came close to losing his colon. Here we see there's so much inflammation. There's so much edema, swelling and narrowing that you can barely see the channel to get through. I added LDN to his regimen and he's been in remission for 7 years, and we see a dramatically improved response. We can see blood vessels, and all the edema and swelling are gone. I reported that in 2014, so more details are there, or in The LDN Book.
In a study in St. Louis on ulcerative colitis, I followed 12 patients with severe to moderate disease who were failing traditional therapy. I gave low dose naltrexone to the patients for 46 weeks on average; some as long as 270, which of course is longer now. One of the 12 withdrew because of insomnia. Half had a good clinical response. Of the 6 responders, 2 of them had been scoped, and the others did not have scoping at the time of the study. They had complete response
Subsequently, I followed 9 patients in the following year who were treated with LDN, and 4 of them had marked to moderate response. One had mild to moderate response, which I never really know what to do with, because it could have been placebo response, so I did not count them. So, 4 out of 9 patients had a significant clinical response, 2 of them with mono therapy, namely no other drug other than LDN; and two who were using additional therapies.
Conclusion: low dose naltrexone for inflammatory bowel disease. It’s a very complicated illness. LDN has low toxicity and low cost. It can be added to therapy, and it's an effective and safe with biological therapy for a prolonged period of time. It can work with the thiopurine, 6-mercaptopurine.
How good it is as a single therapy remains to be determined. Some of the patients I've treated subsequently have not responded, but if I can get a response in even a third of patients just with LDN alone, I'd be very happy. So again, more studies need to be done. It's important to do these studies as randomized control studies, or RCT, because the randomized controlled therapy issues are of really dramatic significance, because even inflammatory bowel disease has significant placebo response. These studies need to be done with endoscopic evaluations to see if the outcomes improve, and there's true healing or not.
Conference presentations an be found here
Keywords: low dose naltrexone, LDN, inflammatory bowel disease, IBD, zonulin, occluding, dysbiosis, Crohn’s disease, colitis, fibrosis, ulcerative colitis, T-cells, cytokines, TNF-α, prednisone, 5-ASA, thiopurines, anti-TNF, infliximab, anti-integrin, vedolizumab, ustekinumab, herbs, probiotics, anti-inflammatory diet, vitamin D, immunoglobulins, toll receptors, methionine enkephalin, MENK, multiple sclerosis, MS