2017 MAP Conference: Treating MAP in Crohn’s Disease

by Prof. Thomas Borody

Prof. Borody is a gastroenterologist who is the founder and Medical Director of the Centre for Digestive Diseases in Sydney, Australia. He has established novel therapies in gastrointestinal areas such as Inflammatory Bowel Disease, Irritable Bowel Syndrome, Parasite infestation, Resistant Helicobacter pylori and C. difficile. In this presentation, he discusses how he treats MAP-driven Crohn’s disease, treatment for fistulae, the synergy of infliximab with antibiotics and antibiotics in treatment-naive patients. Anti-MAP therapy for pyoderma gangrenosum is also briefly discussed. A group of patients have long-term, medication free remission due to Anti-MAP therapy.

Video Presentation

 

Q&A Session

Why do you “ramp up” antibiotic therapy?
Why do you not use hyperbaric oxygen on all Crohn’s patients?
Are there any placebo controlled trials using fecal matter transplant therapy alone in Crohn’s disease?
Do you test for MAP, and if so, what lab do you use?
How do you get such high rates of remission in Crohn’s disease?
What is the difference between rifampin and rifabutin?
A discussion of therapeutic vaccination.
Are there bacteria other than MAP involved in Crohn’s disease?
Why do you include Vitamin D in your treatment regimen?

 

 

Interview with Prof. Borody

Questions and issues discussed include:

What is the difference between treatment naive patients and those who have undergone conventional therapies?
Are there any antibiotic trials for children?
Are there any new treatments coming soon?
What can be done for patients who do not respond to AMAT?
Are there any probiotics or supplements you would recommend?
Will AMAT kill your microbiome?
Is MAP a zoonosis?

 

Presentation Transcript

Good morning everyone. Thank you for inviting me to speak. My name is Tom Borody. I’m a gastroenterologist from Sidney, and I will be speaking today about how I treat Crohn’s disease. I made the title Treating MAP in Crohn’s Disease because that is really what we are doing. So, I have some disclosures that we do run a program in Sidney where we treat patients using anti-MAP. Sometime ago we had a Broad Foundation grant for culturing MAP in people and I had developed some intellectual property and we raised a public company to try and get with Patrick McClean who is sitting over there…there he is and we were able to get 6 million dollars in to this which was a stage one to go forward to have a large company come in and take the licensing forward because I believe as with Helicobacter which was in a similar situation back in the eighties if we don’t get an FDA approval this will not go forward. Next slide.

So, what I would like to cover today with you is what sort of patients do I see and if we can get through the assessment I’ll try and talk about this. But essentially, I see patients who have been seen many times by others. So, I call them the ‘nth’ opinion, and most of them are patients come long having been seen by gastroenterologists here and there and they stop treatment because it doesn’t work or patients who don’t want to take Immunosuppressants, there is this anti-immunosuppressants activity going on out there. Then I will talk about fistulizing Crohn’s and Gaurav Agrawal is here because he developed this treatment and then those patients that those who have never been treated by gastroenterologist forms an interesting group. And then we will talk something about small bowel only and talk a little bit about combing anti-MAP and anti-TNF, I think that’s what we will cover. So just go to the next one.

So, my anti-MAP protocol contains the standard three, but I usually add a fourth and sometimes a fifth. There was a question raised here why can’t we use two and sure if you start treating Tuberculosis with two you are going to get this…we don’t treat two because bugs develop resistance more if you use a smaller number of drugs. We’ve learned that from Helicobacter, we learned that years ago with a first double-blind control trial ever with Streptomycin alone and with Tuberculosis about 30% of the patients would die but when you gave them Streptomycin they developed resistance strains and they all died. It’s worth the read. So I use in ramping up doses, Rifabutin, Clarithomycin, Clofazimine, and Metronidazole, and they start by taking just one of each for the first two weeks then we add one twice daily then in column three you can see bd two in the morning and one at night then two twice daily, so they end up with about 600 mg of Rifabutin, Clarithomycin about a gram, Clofazimine I am now pushing it up to 150, I am seeing papers with patients treated with 600, I wouldn’t go that high but it is probably the best drug. And that’s one of the reasons why I mailed out Clofazimine to a number of you and I had it tracked from a compounding chemist in Sidney just to demonstrate that if you need Clofazimine contact me I will write the script and it can be couriered out to your patients…it is very, very available in the U.S. from us from a compounding chemist that brings it in from an FDA approved plant. So, the way we start the Anti-MAP protocol is to go slow to avoid side effects especially uveitis and we review the patients with a blood test just to look at any leukopenia, liver function test elevation, and on starting I usually halve Azathioprine 6-MP, it’s like if you are treating pneumonia you wouldn’t have immunosuppression going on in the same time, ok. And then we step wise increase and they are reviewed by therapeutic nurses and once the symptoms are reduced and we can push into the higher doses and I now am more and more using in the very ill patients a combination of Infliximab or Humira while we start the anti-MAP therapy. And you all know the side effects, the urine changes color, patients become nicely sun-tanned. Nest slide.

So, the combination of anti-TNF and anti-MAP and hyperbaric oxygen we started because of a patient we had whose fistulae would not close. And each of these three have got an ability to heal fistulae, but none a 100%, not even close. Infliximab at 12 months is 36%, so we combined all those three facilities for treating into patients including hyperbaric oxygen which initially was difficult to organize but we’ve got a large sort of submarine based like hyperbaric unit at Prince of Wales hospital and it was reimbursed, you could do it for Medicare and then of course the minister shut that down, so I went to see the minister and I showed her pictures of fistulae and she said how much would it cost through-out Australia and I said maximum 7-10 million dollars and I told her I thought she would be next Prime Minister because she is good looking and she smiled and she let me have it. So, it’s open up again, it is Medicare reimbursed. So patients start off with the anti-MAP we get enough antibiotics in and I have a fistula for example and then they start hyperbaric oxygen and then we curette I mean we have a surgeon who curettes our fistulae and the big trick there is you can see in the second line there curette fistulae and then you have to compress so when you have a hole and a long line is curetted and bleeding you can compress and pat the two surfaces and that will heal together but if you don’t that will still allow fecal material to go through and that has been our downfall so now I really put pressure on having a good curetting and compression and sometimes I’ll roll a towel after the surgery and three pairs of tight pants and sit them on a bicycle seat once they are awake. Next slide.

So, anti-TNF and anti-MAP synergy and I think we have heard something from Doctor Bach who is here I think today and there seems to be a synergy that the combination does better than each on its own and Gaurav Argarwal noted this synergy with clinical experience in patients, and so we use this now more and more. We get frequent patient referrals with Crohn’s disease and fistulae we treat them with this combination and it has now become a routine protocol. Nest slide.

So, you can see pre and post this is the first, I think, nine patients we had and you get dramatic responses. It was just so hard to believe. The first guy, Chris, over the top left-hand corner, he had internal to internal fistulae, you can see that as you drive in there and photograph. One of those was a rectal vagina, those are a disaster and girls really suffer, and so we’ve got a system for that as well and they just healed up. We had nine out of nine healed. Next slide please.

So, when we combine all of this, it’s kind of repeating what I said before, but the most important is diligent pre-curetting and pressure to help healing that track of tunnels inside the pelvis and then you maintain the healing by having long term antibiotic therapy, so this came out as a small publication of cases and it is now out there so and we have now improved our method by having more of the curetting. Next slide.

So the second thing I would like to talk about is the use of anti-MAP in patients who have never had been exposed to anti-MAP therapy ok, and this was a poster that we had presented at the Vegas meeting last October we will show you these (inaudible). Next slide.

You can see pre-treatment Crohn’s disease activity index score of about 352 in 8 children or 8 young adults they were, the reason I did it is because I had one patient who came along and for some reason we decided just to give him antibiotics, I can’t remember, ah yes, I gave a lecture of this ABC, Patrick you were there, and so this lady thought well he should be treated with antibiotics, the father was a really famous writer of children’s stories and he started on antibiotics and he got better rapidly, so then we did number two and number three. But for an adult gastroenterologist you don’t see untreated Crohn’s patients. That all happens in the pediatric world. So, we try to recruit a pediatrician now to help us do the small, but you can see also on the right-hand side it’s the identical patient before and that’s on treatment. Young guy, you notice how it’s hard for me to point out but in the top right-hand corner, so you can see where the terminal ileum’s opening before and you got this puss sitting everywhere and how clean and nice it looks, you got the ileocecal valve opening here, you can see where the appendix is, and that is up in the ileum afterwards. So, the changes are quite marked, and you can see also the ESR drops, the CRP came down 35 down to 3.1 and the Ferritin goes up and the hemoglobin rises, these became well people. And so, one of the things that I’ve noticed that if we can downstream do a trial in children where you’ve got your naïve patients, treatment naïve patients that may give us the greatest response. Next one.

I just put a picture up. I don’t see a lot of Pyoderma Gangrenosum and I think we have seen about a dozen. But the thing that really makes a difference is anti-MAP therapy. And these are failed Infliximab, failed steroids, failed everything, you put them on anti-MAP, this is four weeks. It heals so rapidly! Next slide.

Small bowel only Crohn’s. It’s a hidden Crohn’s disease. Patients turn up, they’ve got tummy pain, anemia, they’ve been to a lot of people, they’ve had endoscopy, colonoscopy, CT scan often doesn’t see it unless you do CT with contrast. I avoid CT because of the radiation exposure, so we do MRI enterography. And so, we do assessment with MRI, I’m leaving CT there because some people do use it, we do capsule endoscopy, and you can monitor by ultrasound the thickness of the terminal ilea wall. And it gives you a number and as you treat that number falls because the thickness comes down. And this area 5ASA drugs don’t work, you can’t be on steroids forever, you can’t cut it out, so the ideal treatment is to use anti-MAP and initially Infliximab. I put point four down there and some of you will notice …(inaudible) Podolsky? from the New England Journal of Medicine, and I was at a meeting and Dan was speaking and that’s the cause in his publication that ‘Inflammatory bowel disease is thought to result from inappropriate and ongoing activation of the mucosal immune system’ – that all sounds great, but look at this – ‘driven by the presence of normal luminal flora’. So, I said, ‘Dan, look there are 60 of us here,’ – this was in St. Petersburg, Miami area, – ‘and we have always had, we’ve had patients who don’t have any Crohn’s in the colon but have isolated small bowel Crohn’s disease. Don’t you think that if this was a reaction to normal luminal flora you should have the greatest reaction in the rectum, not in the small bowel alone and the rectum left out. It just doesn’t make sense, does it?’ So, Dan said, ‘very good point Tom, let’s talk at the break we’re running late’… well, I tried finding him at the break, I had to go to the bathroom to find him, you know, because he is absolutely wrong. It’s not a reaction to the normal flora, it’s a damn infection that’s causing a chronic inflammation by different bugs that we call MAP. And that’s why I put it in here. It’s one of the nicest pieces of evidence that it is not the cause as he puts it. Now so, I now don’t do just the gastroscopy. You can see this is an enteroscopy. As soon as I have a patient that I know may have small bowel disease, so we use this push ball entroscope, you can see here, this is only two Fridays ago, and the formation of little pseudo polyps, and that’s an early stricture formation, and so you can get in there and get tissue diagnosis. This person was only positive on capsule-endoscopy later on, and my initial enteroscopies, now being started on anti-MAP. Next one.

So, this is another aspect that I wanted to talk to you about rather than drudgery of just normal patients being treated. So, I’ve come across a group of my patients on retrospect who seem to have had a very long remission, between three and 22 years. Off all therapy, no detectable Crohn’s. Anyone out there who is not a doctor would call it a cure. I don’t want to use that term because someone will jump on me, But, as you can see, look how bad the ulceration here is, right? And you can use anti-MAP and Infliximab, we had two groups, four had used anti-MAP with anti-TNF because there was no Humira back then, five with Anti-MAP followed by Fecal Mycobacterial Transplantation, one was treated by FMT alone, this guy came along sick, like 40 kilograms underweight. So, the first things we do is to assess to make sure there is no secondary infection there is no C. Difficile. He had C. Difficile, we started off with two fecal enemas, to get rid of C. Difficile. Well, he didn’t seem to come back for review, so after a few months when it struck me, I called him, and he said, ‘but I am fine I am terrific’. I said, ‘what do you mean? You’ve got Crohn’s.’ ‘Yeah but I’m not taking any treatment, I’ve put on nearly 40 kilograms. And I’ve done the bridge climb’ Which is the Sidney Harbor Bridge, it really takes it out of you when you do that climb, if anyone has done it. He did a bridge climb? He couldn’t even walk upstairs. His legs were like sticks. So, he is the only one who in 28 patients because we present this (inaudible), one FMT seemed to fix him, he’s still fixed five, six, seven years later. I think I know why, his name is Mr. Winner. Happens to be, but you can’t forget that name. Even in Berlin they all laugh. So, one was treated with anti-MAP only and seemed to have got well enough not to have reoccurrence of Crohn’s. So, I think it is a curable infection, except that it is rare, it is maybe some strains that we can cure. So, we observe prolonged disease-free status three to 22 years, patients feel cured, but the significance of this is, that obviously it points to MAP as the cause. Next …

So just to summarize future therapies, I’m running into overtime, I think in the future that we are going to be using more anti-MAP and anti-TNF until something better comes up to achieve early, deep, biopsy proven, mucosal healing. I now then start giving them fecal transplantation. We do ten at home to ten at clinic and then they start doing home infusions. Of course, once our capsules are up and running, we now have a few on capsules, they’ll just go home with two, three capsules to maintain the milieu inside the colon of normal colonic flora hoping that the bacteria there produces substances, antibiotics, bacteriasis, that will maintain the remission. And we’ve got several cooking to get up to three years, so FMT is repeated, and of course we’ve got the promise of immunization coming out of Britain. And that is what I think the future will have. There are other probiotics being developed but that’s pretty early. So, I just want to say thank you to my… next slide

To my group, my team. We’ve got great therapeutic nurses who look after patients in review because I couldn’t cope, and some of the physicians, Gaurav Agrawal, Robert Clancy, Simon Benstock, Antony Wettstein, we kind of work together in maintaining, in bringing the therapeutic response to patients with severe Crohn’s disease. Thank you very much.

Question and Answer Session

Why do you “ramp up” antibiotic therapy?
Well, the reason for the ramping up was brought to me when the paper by (inaudible) came out, Tim Bull’s here? Ah hi, so he would know as well, that was John Hermon-Taylor’s double therapy and they experienced something, eight patients with uveitis. I’ve never had one and I would rather not have profound leukopenia which was levelled at me as a criticism by some of my colleagues and liver function elevation still occurs intermittently so that is the reasoning behind it… may be wrong may be right. I could hit them with 600 of Rifabutin and see what happens, they usually get fevers, admitted to hospital.

Why do you not use hyperbaric oxygen on all Crohn’s patients?
Well, someone just published hyperbaric works in colitis when treated inside hospitals and it could be tried but the delivery of that at least where we are, is more difficult because the guy, Robert Turner, who delivers it for me, he needs to be treating a fistula or a lesion because that’s what’s in our Medicare rules, but I agree with you, I think it could well be done.

Are there any placebo controlled trials using fecal matter transplant therapy alone in Crohn’s disease?
No. there are no trials and there are sporadic cases and probably the best one came from Zhou he’s in Nanjing, I’ll be there talking later this year, but he had patient who had a nasaduodenal infusion, he had an internal fistula, really sick Crohn’s, and even the fistula closed. Hard for me to believe all of that, but there it is. He reports the patient well two three years later.

Do you test for MAP, and if so, what lab do you use?
Yes, I do now. I send my bloods to New Zealand, to John Aitken currently, but there was a long period of time where I had nowhere to test, so I treated everyone who came along. I think everyone will respond provided you look after them. So, I can get very high levels of remission, we’re not sort of getting 65% we’re getting 89-90 because I modify medications, or I add anti-TNF so it is not a clean treatment. One I have to say, and I’m in total agreement with Dr. Graham, we do not have a good therapy for anti-MAP, for Crohn’s, for MAP, we do not have a good therapy and it requires people from this room to trial better therapies. I know that Clofazimine probably the leading drug that we should use, but there is a call, modifying, getting better treatments going. It’s just a hard bug to kill because it is so slow growing.

How do you get such high rates of remission in Crohn’s disease?
What is the difference between rifampin and rifabutin?
Well the Rifabutin, Clofazimine and Clarithomycin combination was published as a (inaudible) combination. I can tell you the publication is by (inaudible). Look it up. And I followed what was published …(inaudible)

A discussion of therapeutic vaccination
Well I have the same question, as I am not an immunizing person, there are no as far as I know, there are no demonstrated vaccinations that are therapeutic vaccinations. Now this is a big reach that John Hermon-Taylor is working on. I think Tim Bull could answer that… (inaudible).

Are there bacteria other than MAP involved in Crohn’s disease?
(inaudible)

Why do you include Vitamin D in your treatment regimen?
(inaudible)

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