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Interviewer: Inflammatory Bowel Disease treatment options. We'll talk about those next on The Scope.

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Interviewer: Dr. John Valentine is an expert in treating inflammatory diseases of the intestinal tract including inflammatory bowel disease. Dr. Valentine, after you've been diagnosed or you've diagnosed someone, I should say, with IBD, is there a standard treatment order that you follow or what can the person expect at that point?

Dr. Valentine: Well, there used to be a misconception that you'd start with the milder medications and work your way up, but people were failing. I think the better concept is to treat to the disease severity. If somebody has mild disease, see if you can get by with some of the milder medications. If somebody has obviously severe disease, you're wasting your time starting slow and the patient's going to get into other kinds of problems. It also makes a difference if you're talking about ulcerative colitis or Crohn's disease.

Let's start with ulcerative colitis. I would like to see everybody fail a class of drugs called mesalamine back in the '50s, '60s, and '70s, a drug was called sulfasalazine. That still exists, but they all deliver the same medication to the colon. Most patients will respond well to that. There is a proportion, 30-40% of those, that that class of drugs isn't enough. Then they need to get into medications to suppress their immune system.

We may use steroids such as prednisone in patients just to get them better quicker while you want to see if the mesalamine drugs will be effective for them. But if they're not effective, then steroids can give some prompt relief, but they're not good for your long run. They are full of complications.

Then we get into what we call steroid sparing therapies, which could include azathioprine, methotrexate, or anti-TNF medications, infliximab. Vedolizumab is a newer so-called biologic, but that blocks the signal that sends the inflammatory cells to the intestine.

Interviewer: Are there any drawbacks to those medications?

Dr. Valentine: Well, with the mesalamine medications, they are very safe. Every drug has potential side effects to it, including aspirin, but these drugs, like I've said, have been around since the '50s in one form or the other. So they have a long track record and they're very well tolerated for the most part. When you start getting into the medications that suppress the immune system or blocking a key component that we have for a reason, given what we're doing to the immune system, I think there are also surprisingly well-tolerated. But you do need to be aware of potential complications.

So we avoid chronic steroids because of effects on mood. You can get depressed, trouble sleeping, get irritable. It can push you over to be diabetic if you're prone to that already, weight gain, acne, other cosmetic changes can occur, as well as osteoporosis from long-term use. So we need to avoid long-term use of steroids.

The other medications, methotrexate, azathioprine is a therapy and we'll start with those. They can reduce your white counts so you need blood monitoring. Abnormal liver tests can occur with both of those so you need to monitor the liver enzyme. Look for irritation of the liver. There's also an increased risk of skin cancers and lymphoma with patients on azathioprine. Now, it's not dramatic, but there is an increased rate and patients need to be aware of that.

So then, you get into the anti-TNF medications. These are monoclonal antibody or biologic drugs that bind the protein in your immune system called tumor necrosis factor, which is very stimulating to the immune system. While there appears to be less of a risk of malignancy with those medications, it's not zero. You need to screen patients for exposure to tuberculosis because putting somebody who has been exposed but not been treated can let the TB run wild. Screening for TB and for Hepatitis B is very important for that class of drugs.

Interviewer: Sounds like some of these cures are just about as not fun as inflammatory bowel disease is.

Dr. Valentine: Well, if you don't need to be on those medications, you shouldn't be. But I think if you need them, the benefits outweigh the risks.

Interviewer: Got you.

Dr. Valentine: While these complications can occur, they're not very common.

Interviewer: That's good. When it comes to the treatments, it's all about just managing the symptoms or is it about actually suppressing the disease?

Dr. Valentine: It's suppressing the disease. You might be able to manage the symptoms with pain medications, antidiarrheal medications, but the inflammation is still there and problems will occur.

Interviewer: Yeah, all right. So let's talk about if you're diagnosed with Crohn's Disease, then. How do the treatments differ?

Dr. Valentine: So since Crohn's Disease likes to, or commonly affects, the small intestine, the mesalamine drugs don't work very well because they're designed to deliver to the colon. In addition, with Chon's Disease, rather than being just the lining of the bowel that's inflamed, the whole thickness of the bowel wall is inflamed so you need more potent medication. Mesalamine medications don't work very well for Crohn's Disease. Very mild, colonic Crohn's, I've seen it'd be effective. But if you have more severe disease, you need to move on.

The only thing to move on now is to immunosuppressant medications. The same ones I mentioned before. The azathioprine, methotrexate, the anti-TNF drugs, infliximab, adalimumab, certolizumab, and then the vedolizumab, the one that blocks the lymphocyte traffic, has also been approved. There have not been head-to-head comparisons, but it doesn't appear to work as well as the anti-TNF medications. So because you need to get into more aggressive medication, and because of the complications with Crohn's, you don't want to let that drag out too long.

Interviewer: What's somebody's eating or their lifestyle, or are there any changes they could make there that will help inflammatory bowel disease, or is that not even related?

Dr. Valentine: There are some things you could do to help the symptoms. So when you're bowel's inflamed, especially the colon, the job of the colon is to absorb water and to hold your stool until it's a convenient time to get rid of it. When it's inflamed, it's having a hard time doing that so certain foods that pull more water into your colon are going to give you more symptoms. So we advise people with the inflammation of their colon to avoid raw fruits and vegetables, high fiber foods until we get the inflammation under control.

Once it's under control, you can add that stuff back to your diet and tolerate just like before your diagnosis. In Crohn's disease involving the small intestine, but when the whole thickness of the bowel wall is inflamed, the lumen, the center part of the intestine, actually gets narrowed. So again, bulkier, fibrous foods may have a harder time getting through the narrowing, which give symptoms of abdominal pain, distention, and if bad enough, nausea and vomiting. So again, avoiding those until we get the inflammation under control is often recommended.

Interviewer: But it doesn't actually treat the problem, which as you indicated, if untreated, could cause bigger problems?

Dr. Valentine: Correct. I firmly believe we need better dietary studies in inflammatory bowel disease, but the studies that have been done to date haven't really identified any particular diet or lack of things in your diet that causes inflammatory bowel disease.

Interviewer: Are there any other common things that patients say to you that they wonder if it will help as opposed to taking some of the medications that you recommend? And what do we know about those?

Dr. Valentine: Diet comes up a lot and I think patients are frustrated and disappointed when I can't tell them how to change their diet. Probiotic supplements also come up frequently and in the test tube, they do have anti-inflammatory activity. But there are thousands of different species and strains of bacteria within the gut.

Most of the probiotic supplements have between one to 10 species of bacteria and we don't know which ones and how many and which ones you need for which disease processes. So they won't be harmful, but I really would have difficulty going to the medical journals and finding clinical trials of probiotic supplements showing they're of great benefit.

Interviewer: What can a patient expect for the rest of their life, then, since this is something that you manage and treat throughout the rest of your life as far as dealing with inflammatory bowel disease?

Dr. Valentine: Well, the need to stay on chronic medication and keep regular follow-ups with the gastroenterologist is important. Because we can't cure this, chronic treatment is needed. Then, if you have inflammation in your colon, after you've had the disease for about 10 years, you need to get into colon cancer screening surveillance programs because of the higher rate of colon cancer that's found in these patients.

So typically, it's a colonoscopy every two to three years after 10 years, and then current guidelines recommend a yearly colonoscopy after 20 years of inflammation in the colon. So if you have Crohn's disease only in the small intestine, the rate of colon cancer is not increased. That's another reason why to determine where in the bowel the inflammation is occurring.

Interviewer: As far as my lifestyle, if I'm on the medications that are managing the symptoms, it's taking care of the inflammation, which is the root cause, life relative is normal beyond that point?

Dr. Valentine: Except for having to remember to take your medication.

Interviewer: Yes.

Dr. Valentine: That is easy to do when you feel bad, but then when you're feeling well, you have to remember to take it.

Interviewer: Take that medication and you'll be fine.

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Interviewer: Donor matching for fecal transplants, we'll talk about that next on the Scope.

Announcer: Examining the latest research and telling you about the latest break throughs. The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. June Round, assistant professor in pathology at the University of Utah. Dr. Round, I think most people have heard about fecal transplant by now, but how effective are they really?

Dr. Round: So I think people have heard a lot about fecal transplants being for clostridium difficile infections. So they work quite well for this kind of transient infectious organisms.

However, people have started to try them for other intestinal inflammatory diseases like inflammatory bowel diseases, such as ulcerative colitis or Crohn's disease and they are less effective. And I think if we now understand how these microbial communities are shaped will help us to better understand how we can make fecal transplants more effective in the future.

Interviewer: And that's a good segue to your research. You did fecal transplants in mice and got some very different results depending on how they were done.

Dr. Round: So we're working with three different strains of mice, so they kind of represent three different people. But you infect them with the same amount of salmonella, which is now a fairly low dose, something that a human might take from contaminated food and some of these animals would dropped dead within two days.

Interviewer: Oh, my gosh.

Dr. Round: Other animals would live well over a week and actually clear the infection, so the differences between the susceptibility or resistance of these animals is really huge. And of course there was the third animal which had a very intermediate response. They didn't drop dead, but they got very sick, had a lot of diarrhea, but eventually cleared it after a couple of days.

Interviewer: This is just sort of their response before the transplant, is that correct?

Dr. Round: That is their baseline response right before the transplant, that's right.

Interviewer: Okay. And then once you did the transplants, what were the differences you saw there?

Dr. Round: So the animal that was highly susceptible, the one that would drop dead after two days after salmonella infection, if you give the fecal transplant from the highly resistant strain, that susceptible strain now became highly resistant. Meaning that instead of dropping dead after two days, it was able to live for well over a week and then clear the infection. So you can essentially make a susceptible animal highly resistant by simply giving it a fecal transplant.

Interviewer: So what was different about these different fecal transplants?

Dr. Round: The difference between the fecal transplants was that they came from animals that had a different suite of immune genes, and these immune genes are called Major Histocompatibility Complex or MHC, so there's lots of these MHC genes. So express multiple MHC genes and the very different throughout the population.

Interviewer: So maybe a little bit like we have different blood types, but more complicated than that.

Dr. Round: That's a great example.

Interviewer: Do your findings suggest that people with a certain MHC profile will always combat certain infections better than others?

Dr. Round: The major point of our paper is really that your MHC type dictates the type of microbes that live on your body. So some people I have an MHC type that selects for really good robust organisms that help them fight off salmonella really well, whereas other people might select for organisms that don't allow them to fight off salmonella very well. The same could be true for some . . . that's why some people get inflammatory bowel disease, some people don't, is you're selecting for just different cohorts of microbes.

Certain MHC types are associated with certain infections. Now, people always thought that that was because the immune system was presenting a better suite of antigens and mounting a better immune response. That's what has been thought for decades and decades, so our findings suggest that it's beyond that actually, it's that the MHC is selecting for microbial communities and some microbial communities are better at helping us battle infection.

Interviewer: I've been learning about certain companies that are making so called poop pills, where they take healthy donors and offer those as fecal transplants for, I think, right now it's mostly for people affected with the sedate. But what you're saying is that if they did an additional screening step it may help those therapies work better.

Dr. Round: Yes, I think for things like infections where the infection lasts a week, it's a very short time frame. I think that the best thing to do would be take it from a very resistant person, resistant to that particular infection because they probably have microbes that are able to fight the infection off.

In our case we were testing salmonella infection. Now, if you want to think about the broader picture, the implications of our findings, although I will say that we haven't quite tested it, is that perhaps for more chronic diseases like inflammatory bowel disease you might have to MHC match for microbes.

Interviewer: The MHC complex and what it does is the same system for like graft versus host when you donate a kidney for example you have to make sure that you have a match.

Dr. Round: That is exactly right.

Interviewer: And if you mismatch then you reject that graft.

Dr. Round: The one thing that's becoming evident is that you can give probiotics to people. You can give them millions and millions of bacteria in a little pill, but it doesn't always stick in the gut. It kind of gets flushed through. And part of that could be because that person doesn't have immune system that selects and allows for that bacteria to live there.

The same is true for fecal transplants. A lot of times to give a fecal transplant to someone and it works for a little bit, it stays in the gut of those people for a little bit, but then eventually those organisms get either competed out, flushed out, they're just not selected for.

So our findings suggest that perhaps we can make fecal transplants stick a little bit better if maybe we match the MHC donor to a recipient. We keep talking about this idea of personalized medicine and I think as far as personalized medicine is concerned, we're going to have to couple the genetics of the person, which is going to include the genetics, their immune profiles as well.

We're going to have to couple the genetics with the person along with the types of microbial communities. I think if in the future we can put those two together that we can have some really powerful therapeutic interventions in the future.

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Scot: Go to the dentist and get diarrhea? It doesn't make a lot of sense, but it happened to my Mom. She went to the dentist, they needed to do a procedure, they gave her some antibiotics and then a couple of days later she started having terrible diarrhea that persisted for a long time. She went to her doctor; they gave her a couple of different medications. Nothing quite seemed to work, except for this really expensive last resort. Dr. Tom Miller, what did she have?

Dr. Tom Miller: Scot sounds like she had Clostridium difficile colitis or diarrhea. And this is caused, it's commonly known as C. diff.

Scot: Yeah, that sounds familiar.

Dr. Tom Miller: We just call it C. diff. It's an increasing cause of prolonged and difficult to treat diarrhea and it's caused or triggered by certain antibiotics that are used to treat common infections, like strep throat or urinary or bladder infections or skin infections.
And what happens is when you take common antibiotics, they not only tackle the infections they are intended to treat but they also kill some of this normal protective bacteria and it's not a bacteria that we normally see in what we call colon carpet bacteria, but once it sets up shop it starts to produce a toxin in certain people, especially those people who receive antibiotics, and that toxin causes diarrhea and left untreated it can be life threatening.

Scot: So, if I get antibiotics, is that something that I need to worry about or only if I'm a carrier of it currently?

Dr. Tom Miller: If you are a carrier, you are at higher risk to get it if you take antibiotics.

Scot: Is C. diff contagious? My Mom said that her physician said it was highly contagious.

Dr. Tom Miller: The problem with C. diff is that it continues to exist on surfaces as spores and so it's hard to kill and so that's why healthcare centers or health centers and hospitals have higher rates of C. diff because it's hard to kill so we have to be very careful about hand washing and hygiene and sterile cleaning of the rooms and all of the pieces of furniture in a place where a person who has this type of diarrhea.

Scot: So what can be done? Like I said, my Mom I think it was for a two week supply of pills spent $1,200.

Dr. Tom Miller: Well, the other part of this is it is hard to treat and it requires prolonged treatment and sometimes repeated courses and treatment of different antibiotics which can be very expensive. So, this is a problem that we're facing nationally and again there are some take home tips for people.
Don't request antibiotics indiscriminately, don't use prolonged courses of antibiotics unless it's clinically indicated and directed by your physician and make sure you let your physician or dentist or healthcare provider know if you've had Clostridium C. diff in the past because they need to take precautions that you don't develop it again or watch for it.
And seek attention if you develop diarrhea lasting several days after completing the course of antibiotics. There's a test that can show if you have C. difficile toxin and this will direct your provider to treat you for it.

Scot: So, if I was concerned and my provider said you should be on some antibiotics and I was really concerned could I ask for this test?

Dr. Tom Miller: Right, I think the key thing is to describe the symptoms and what's going on to the physician and work with them to decide what the best course of action is. Many times people that take antibiotics will have diarrhea that lasts just a few days and then goes away, just simply due to the antibiotic.

Scot: How do I know that it's not in my stomach and if I take the antibiotics that I have been told to take that I'm not going to come down it?

Dr. Tom Miller: Again you don't really know. I guess my point is if you need those antibiotics for say strep throat or a bladder infection, then you need them. It's up to the physician to choose wisely to select an antibiotic that has a lower incidence of causing C. difficile colitis or diarrhea.

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Interviewer: We're talking with Dr. Steven Guthery, a gastroenterologist that sees some of the toughest medical cases, kids with rare and undiagnosed diseases. Dr. Guthery, can you explain what a rare disease is?

Dr. Steven Guthery: A rare disease has been defined variably. In the United States, it's defined as a disease that occurs in fewer than 200,000 Americans. There are a variety of publications that estimate the number of rare diseases. So there's anywhere from 5,000 and 8,000 rare diseases. These individually can be quite rare but in aggregate, if you take all rare diseases and clump them together, they're actually common as a group.

Interviewer: So what is an example of some of the cases that you see in your clinic?

Dr. Steven Guthery: We see a variety of rare diseases that occur predominantly in the gastrointestinal tract or the liver in children. Examples of this include primary sclerosing cholangitis, which is inflammatory problem of the bile ducts of the liver. We see rare conditions such as biliary atricia, which is malformed bile ducts of the liver in particularly infants. There's an estimate that about 5 per 100,000 children have biliary atricia. That's in comparison to something like coronary artery disease, or heart disease, which occurs in about 6,000 per 100,000 individuals.

Interviewer: Can you give an example of what some of these kids are going through?

Dr. Steven Guthery: As they grow, many of the children have frequent visits to the doctors, frequent hospitalization. Some may require multiple operations. We have patients who occasionally have multi systemic disease so it may not only be their intestine or their liver but it may be their brain, maybe their heart, maybe their lungs, so they may end up traveling from doctor, to doctor, to doctor over time.

Interviewer: What are you researching in this area?

Dr. Steven Guthery: We've been increasingly interested in understanding what's a rare disease. In Utah we have this very unique sort of healthcare system for the kids. The vast majority of children that live in Utah receive their care at Primary Children's by University of Utah physicians. We have the ability to count up the number of children with disorders and then sort of say that's a rare disease, that's not a rare disease. For example, one our trainees, Dr. Mark Dunnell, who's now at the University of Manitoba, was able to establish essentially that disorders that he was interested, which are immune disorders of the liver in children, are rare diseases.

Interviewer: What does that do for you? What can you do with that information?

Dr. Steven Guthery: It opens up the door for a variety of research initiatives, research dollars, maybe even industry interest in the disorder. The Orphan Drug Act was passed in the early 80s. It offered the pharmaceutical industry incentives to develop therapeutic products for rare diseases.

Interviewer: Yeah, I hadn't really thought of that aspect, that you really have to champion these diseases to get the support to help these people.

Dr. Steven Guthery: Everything we learn about ulcerative colitis in children we learned in adults. The number of adults overwhelm the number of children. Policies are driven towards those adults. Healthcare plans are driven towards those adults. Drug development is geared towards those adults with the condition. So you do have to champion the subset of children that have it.

Interviewer: So what's an example of that?

Dr. Steven Guthery: For adults, 13 and above, they can swallow a pill. A child may not be able to swallow a pill. In order to get that medicine to them they have to either open it up and sprinkle it on some pudding and it may only a single product that you're able to open up. Well, that particular product may not be covered by the child's healthcare insurance or it may need to be compounded and for some reason it's extraordinarily expensive or complicated to compound it into a suspension so the child can take it. So we end up having to jump through a variety of bureaucratic hoops just get the medicine that the child needs.

Interviewer: You also see patients who have undiagnosed diseases whose disease defies category. What can you do for them?

Dr. Steven Guthery: Some patients that have undiagnosed diseases actually have a diagnosable condition. It just takes them awhile to arrive at that diagnosis and there are a variety of factors that can contribute to that delay. There's a subset of patients and I think that, particularly in pediatrics where there's a lot of patients that are being referred in, many of us encounter patients that have no known diagnosis. For those patients, we're beginning to study them in terms of, especially if it appears as if they have a genetic illness before genome sequencing, for example. But there are other newer technologies that undiagnosed diseased patients can have access to in a research setting.

Interviewer: Have you used whole genome sequencing to solve an undiagnosed disease?

Dr. Steven Guthery: Sometimes a disease is so rare that only one person exists, and if I talk too much about it it's identifiable. I can give an example without giving too much detail. We have a patient that several of us took care of that had multi system disease and lived for 10 or 12 without a diagnosis and the treatment was actually successful. They appear to now have maybe even a cure. Then now we go back in time and say, well, can we make a diagnosis here? We used whole genome sequencing on a research basis and were able to identify the cause of this child's condition.

Interviewer: Oh, really? So you found the disease that they had.

Dr. Steven Guthery: When you do these experiments you find tens, if not hundreds, of genetic changes. You have to use intuition, science, and informatics to whittle that list down to try to be able to test the hypothesis that that genetic change is causing the child's illness. A variety of things happen, including another group published the same mutation in another child in Japan. The mutation occurred in a gene that we know, when you have mutations in that gene, you can get human disease. So that was another piece of evidence.

Interviewer: Now that you have that mutation, can that be put in the body of knowledge?

Dr. Steven Guthery: This is technically a patient that had an undiagnosed disease and has subsequently sort of has a new disease. It's a process that really drives scientific discovery. One thing, from the care side of things, is can you design, for a patient that has multi system, a new healthcare delivery method.
For example, you have a patient that has multi system disease. This patient had three systems. They're going to see three or maybe even four doctors. That's hard. Not only is there uncertainty but you have to make appointments to see them and maybe, if they live far away, they may have to come down and see one doctor one day and the next doctor three days later. So trying to coordinate care can be a challenge. So can you develop new ways of delivering more efficient care for those patients? That's one sort of thing that we learn from just a single experiment. That's not rocket science. It just became very apparent that if you can bring people together at one time just to look at a patient then it really improves the patient's care.

Interviewer: Right.

Dr. Steven Guthery: If they have a new disease then suddenly you have the ability to take the information and put it into the body of knowledge. Specifically, if this particular patient had a mutation in a gene that may be important to a more common illness, and so can you generalize that finding to the more common illness and find out if that gene's pathway is important in the disease? We also use that information to help develop new bioinformatic tools to go through genomic data. So just that one experiment drove sort of thinking on how we deliver care. It drove maybe a new biologic process that's important to more common disease and it also drove the assistance with the development of newer technologies sort of in this realm of genomic medicine.

Interviewer: How do you think treatment for rare disease might change in the next 10 or 15 years?

Dr. Steven Guthery: I've been thinking of this analogy about Southwest Airlines and how they move lots of people from city to city. Because of the volume of passengers moving from Salt Lake to Denver they are an infrastructure to be able to move those passengers quite efficiently. That analogy serves for healthcare. For example, many of our processes or treatments are geared towards common illnesses, but for patients with rare diseases it's sort of like there are two to three passengers in rural West Virginia that may need to get to rural Montana. There's no efficiencies or good systems to move patients from small town to small town.

Interviewer: So what can you do for those two people?

Dr. Steven Guthery: They need a Learjet and somebody has to be willing to pay for the Learjet.

Interviewer: Yeah. Well, how do you design a Learjet for rare disease patients?

Dr. Steven Guthery: I think that the first important thing is to understand that those patients are fundamentally different. Patients, families, and physicians must advocate for those patients that have rare disease. They must be advocates not only in developing new research treatments, developing new science, but they also must be advocates for themselves, for their family members, or for their patients to navigate the healthcare system. They almost have to be sort of taken out of the machine and put into a specialty care center. It's not Walmart, it's the neighborhood boutique.

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