Good evening everyone and welcome to tonight's webinar, Treatment of K9 IBD Novel Developments. Tonight's webinar is free access for everyone to view thanks to the very generous sponsorship of Purina. We're working closely with Purina this year to provide the highest quality CPD, for your enjoyment.

We do have, Libby Sheridan, from Purina who's online with us, who's just gonna say a few words before we begin. Thank you very much, Paul, and good evening everybody, and I'm so pleased to be able to welcome you to this Purina sponsored webinar and we're delighted to have someone so eminent in the field of gastroenterology presenting tonight for us, Dr. Karen Alansbach.

So she's come all the way from the USA online. This is going to be the first, as Paul said, in a series of webinars that we're sponsoring, and to be able to support you in delivering a really great service in practise to your patients. So I won't hold anything back any further and I'll hand you back to Paul and to Karen.

Thank you. Thank you very much, Libby. So we're delighted to have Professor Karen Alan Smack speaking tonight on this very important topic.

Professor Alan Smack received her veterinary degree from the University of Zurich. She did an internship in small animal emergency medicine and critical care at Tufts University, and a residency in small animal internal internal medicine at the University of Pennsylvania. She was awarded a PhD in Veterinary Immunology from the University of Bern in Switzerland.

For her work on canine chronic enteropathies. She's also a board certified internist, and currently appointed as professor in small animal medicine at Iowa State University. Just, a little bit of housekeeping before we do begin.

If anyone has any questions, please do feel free at any point to submit them into the Q&A box, which you should see on your screen. If you can't see that box, if you just hover your mouse over the presentation, the icon should pop up. There is also a feedback survey at the end of the presentation.

So it'll only take a minute or two of your time if you, if you can fill that in, it's much appreciated, helps us to plan future activities and future topics, and so forth. Please feel free as well to engage, on social media, tag us in Twitter, Facebook, and so forth, and include Purina to let, everyone know that you're listening in tonight. So without any further ado, it's my pleasure to hand over to Do Professor Karen Allensbach.

Thank you very much, Paul. Good evening everybody, and I'm glad you're online tonight. We're gonna be talking about treatment of canine inflammatory bowel disease and some novel developments and just to start you off, I'd actually like to pull some of you to find out how often you actually see chronic diarrhoea cases.

Is this something That you fairly commonly see or not. And in my mind, also it can quite rapidly turn into a diagnostic conundrum and can be a bit of a frustrating disease to diagnose as well as to treat. So, I just like to pull some of you to see how often you actually see that.

So we'll wait a little bit until we get these answers back. Yeah, so the poll is now live. We have about 60% of people voting.

OK. So just give everyone 15 to 20 seconds to make sure the votes come in. OK, so we have about 75% of people have voted.

Now 29% of respondents have said they see these cases very often. OK. 63% of individuals have said fairly often.

Yeah. And 8% have said hardly ever. Hardly ever.

OK. So we're in the fairly often with most of you, but 30% actually seem to see it, quite commonly as well. So, that's good.

So it looks like it is definitely of concern for you out there in private practise. And then how many of you are frequently frustrated with the World Cup, and also the treatment of these diseases? So just let that run for another 15 to 20 seconds.

Great. OK, so it seems to have slowed down. So 78% of respondents have said yes, they are frustrated.

78%. Excellent. So it looks like we have a large percentage of you online today who are frustrated with this and so hopefully we can help this a little bit with giving you some information and hopefully some some tips as to how to handle these cases in private practise.

So, just to go back quickly about the diagnostic approach, one of the things to realise, of course, is that once we're dealing with chronic diarrhoea, the definition of that is that it's been going on for at least 3 weeks. It can also have been intermittently, but in general, it means that symptomatic treatment and maybe anti-parasite treatment hasn't worked and it's slowly but surely progressing over being on for at least 3 weeks. And so that's when we call it chronic diarrhoea.

So these cases in my mind, need a little bit more to time to chat to the owners and so it's, it's one of the things to potentially set aside a little bit more time than usually for your private practise appointments to talk to owners about what kind of options we have regarding diagnostics, but also treatment and so that they know what they're in for and, and we're gonna be talking about this obviously later on as well. So the things that we can do, I've listed them here and we're just gonna go through them quickly. Obviously, you want to get rid of GI parasites before you go on and do anything a bit more involved and maybe more expensive as well.

I would say that's probably really more of a problem in younger animals, of course, and, and those who get reinfections very commonly. And I would also say that it's usually not something commonly seen with helmins. So chronic infections are not usually a disease that we see with these parasites.

Giardia is obviously one that can cause chronic diarrhoea. I would say though that a lot of times it is sort of an additional problem and will not Be your actual underlying disease process. So it is important to kind of realise whether those are recurring infections or whether we're actually just talking about something that we found incidentally, if you will, and that there's an underlying disease process like for example, inflammatory bowel disease that you have to address as well.

The next step is, is, of course, to look into bacterial pathogens, and I'm not sure how often you in private practise will be doing culture, of faecal material to look for, let's say, infections such as Campylobacter and salmonella, which is the classic ones to try and rule out. Now that it's obviously become more available to do quantitative PCR with the panels that are available out there, I think it's become even, more often, that we actually have results available that we have to interpret on these pathogens. And again, it's kind of similar as with the situation that we've been talking about with Giardia.

A lot of times. If you have Campylobacter or salmonella, it's gonna be something that's almost an incidental finding. So a lot of times these animals with chronic diarrhoea will actually have a shedding going on of these bacterial pathogens and are not therefore actually infected and it's not really causing their underlying chronic diarrhoea.

Also keep in mind that, of course, with salmonella and Campylobacter, these diseases, if they're, you know, if they are acutely infected, actually present as a food poisoning case. So they're severely sick. They have acute vomiting, diarrhoea, bloody vomiting, diarrhoea, and so that's not commonly what we see in chronic diarrhoea.

So just be aware of that, and, you know, don't overinterpret it, especially with the new QPCRs that are available now. And then if we're talking about small intestinal diarrhoea, most commonly, we're also gonna be talking about metabolic diseases, not just GI diseases, and so those need to be excluded. In dogs, we're mainly talking about kidney disease, liver disease is possible as well, and Addison's is always one to potentially consider.

So something like a basal cortisol level is always a good idea if that's on the list or you're suspicious for it. The next thing is exocrine pancreatic insufficiency. So, that's obviously an easy one to try and exclude with a serum TLI test.

If you're suspicious, again, if it's maybe a younger dog, sort of 23 years old, and, if there's a pre, a breed that, could be affected more commonly, although I would say that We see EPI in all sorts of breeds these days, so don't let yourself be fooled by that. You know, it's always a good idea to do a TLI if you have clinical signs that fit and classically with EPI you would actually have some type of polyphagia. So that's not commonly seen with other types of chronic diarrhoea.

And if you have that, then I would definitely test for it. And I think those are probably the tests that I would do at first. And at that point, it really depends how you want to proceed, whether you now want to do an actual treatment trial, either with diet or even antibiotics, and that's kind of fallen out of faith.

A little bit. We'll be talking about that a little bit later on as well, because we're really not quite sure what we're treating with antibiotics and of course we're quite concerned these days that we're just increasing antimicrobial resistance and not really actually treating these cases appropriately. And I guess at the end of the day, depending on what kind of workup you've done and how far you've come with the owners to discuss this, you will then proceed and take intestinal biopsies either endoscopically, or with, with laparoscopy or laparotomy.

And I, depicted that as a, a garbage diagnosis because I'm still to this day frustrated about the pathology reports that I frequently get from these cases which will tell you something like mild to moderate to severe lymphoplasma cellular infiltration, and that doesn't tell us anything, of course, as to how to treat these cases and I think that's one of the problems that we have with them. So we're gonna be talking about this a little bit more over the next hour. So the main causes for chronic diarrhoea in dogs are food responsive diarrhoea, as well as antibiotic responsive diarrhoea and inflammatory bowel disease.

And depending on which book you read, some people will say that inflammatory bowel disease is kind of, the overarching kind of term for all of these. And, some people actually think that inflammatory bowel disease, that term should be reserved for those that actually need immunosuppressive treatment. Regardless, it doesn't matter, at the end of the day, it's really about what kind of treatment we can give them and which subsets of these three diseases, so that we can and try and make them better.

And one of the things that's important to realise in that context as well is that all of these three look the same on histology, so they will all show up as lymphoplasmacytic and or eosinophilic IBD. And with that, I mean, mostly lymphoplasmacytic, maybe with a few eosinophils, and that's really what we most commonly see with the diagnosis of inflammatory bowel disease. Dos.

Of course, there's also always a possibility of neoplasia. We're mostly talking about diffuse lymphoma cases and, and that's obviously a concern. And then depending on where in the world you actually practise, probably not so much in the UK, but if you, if you're in the US also some fungal diseases, of course, are on the list such as histoplasmosis, and Picium for example, as well.

So these Sort of things really do need to be addressed before we call something IBD. So at the end of the day, you can see inflammatory bowel disease is called idiopathic, and it's called idiopathic because you have to do a quite an extensive clinical and diagnostic exclusion diagnosis. And once you haven't found any of the things that we've discussed, then you can call it inflammatory bowel disease.

So what do we do once we have that, so going back to some of the recent research that's been done in canine inflammatory bowel disease, and it does look like there's definitely different things involved in the pathogenesis. What we know about this particularly in some breeds like the German shepherd dogs and also in boxers with hisytic ulcerative colitis where it's now called Granulomasus colitis, we do see immunoregulatory defects, so the genetics do play a role, especially in some breeds. We also know that there's defects of the mucosal barrier, as to, that they're more leaky, in their gut barrier, and that can also lead to protein losing enteropathy, which we're also gonna be discussing a little bit today.

And then, we also know that antigens from the food and from the microbiomes. So anything that's inside the intestine really contribute to all of that as well. And as we know, all of these things obviously we're trying to influence with the three mainstays of treatment that we have for inflammatory bowel disease and those are antibiotics or probiotics.

We'll be talking about that a little bit, food elimination diet, of course, and also immunosuppressive drugs and all of those, will be going into a little bit. So one of the things that I always talk about is that I think it's a really good idea to have a little bit of an knowledge of the epidemiology of chronic diarrhoea in your head because if you're seeing these cases in private practise, it's nice to have some kind of clinical picture that you can try and associate with the case you have in front of you. And that gives you an idea of how likely is this case that I'm seeing right now.

To be either food responsive or steroid responsive, and I think those are really the most important things to try and discern. So this is data from a while ago from a study that I've done my PhD on, which was at the University of Bern. We had 65 cases, we had various breeds involved and what we had there was a prevalence of 65% of dogs with chronic diarrhoea that were food responsive.

And really only just about a third of all cases that require penicillin. And at the time, that was actually looked at as something a little bit weird, and I think a lot of referral veterinary institutions weren't quite sure whether they would believe this because they thought they see a lot less food responsive diarrhoea. Cases and it's interesting that actually since then we've been confirming that and there have been several new papers coming out actually showing that that's the case even in secondary and tertiary referral institutions and that's an interesting fact actually because thinking that this many dogs coming in to see me, let's say Somewhere like the Royal Vet College, you know, where we usually see them as a secondary or tertiary referral centre and still so many dogs will be diet responsive.

I do think it's a huge concern with compliance with these owners and so it's one of the things that you can definitely do something about to try and address out there in practise. So the population statistics, when we look back at that study, it was interesting to see. We did have younger dogs in the group of food responsive disease, so they had about a mean age of about 4 years, and for the IBD group, which was the group that needed immunosuppressive treatment, the age group was more about 7.5 years.

So, and that's consistent and that's actually been shown in several other studies as well. So you Usually if you have younger aged dogs, they're more likely to be food responsive. The other thing that we saw was that the weight of the dogs that needed immunosuppressive treatment was significantly lower, and that was probably due to the fact that we had quite some PLE cases in that group, protein losing enteropathy, and these cases are more commonly seen, I think, in small breed dogs, Yorkies, Westies, these types, and so that's probably why the weight difference there is so obvious.

What was also interesting to see in this group of dogs was that the clinical activity index before and after treatment with food responsive disease actually did come down quite nicely as you can see, from about 1 of 6 clinical activity index down to about 1, so almost no. And you know, that's really clinically considered minimal disease, so that's something that people very much can live with. However, if we, if we're talking about immunosuppressive treatment, it's not quite so good.

They do respond, so they go into remission, but not quite as nicely, and many of them after treatment will still have an activity. Index of about 3.5.

So, they might still have a little bit of loose stool, but maybe still going well otherwise and eating and and doing well. And so these are the things that are also nice to know about so that you can set expectations when you talk to your owners in practise. The other thing that is really important to realise here and that's another thing that we've confirmed with more studies later on, is that it actually does not take very long for chronic diarrhoea cases put on elimination diet or hydrolyzed diet to respond.

And if you think about all the books that have been stating for years and years that we need to put these dogs on diets for 6 to 8 to 12 weeks depending on what you read, I think that's really out of date. I think that's not true. Most of these cases will respond very, very quickly within 10 to 14 days, and that's a good thing to know about because you can let your owners know out there that, you know, we're gonna try this, but you don't have to give it forever.

If it doesn't work within 10 to 14 days, then we can go on and we can go and look for something else because it then it's not likely to be food responsive. And I think that's a very good fact to know about. And also important, this just goes for chronic diarrhoea.

It does not go for any food allergy, dermatological signs that you might have as well in these dogs. Those dermatological signs, pruritus and things like that do usually take longer, so, not to be confused about these two things. So the clinical picture for food responsive disease, if we consider this the old data, sort of going back to about year 2007.

So clinical signs are usually more mild, many dogs show colitis signs actually, large intestinal signs, and they seem to be more large breed dogs and also younger dogs. So, those will be your classic food responsive disease cases. Now, we've recently done another study at the Royal Vet College where we included in a retrospective study 203 dogs, that we've seen over a period of about 6 years.

Again, all of these have persistent gastrointestinal signs, so they all had chronic diarrhoea, and we, were not able to document any other causes for gastro. Signs, so they were clinically diagnosed for inflammatory bowel disease. And we also had histological diagnosis which confirmed lymphocytic plasmocytic, or mild osinophilic enteritis, so consistent with IBD.

And then what we did with these dogs was that we had a Protocol where we put them on an elimination diet or hydrolyzed diet, and if they responded within 2 weeks, then they were kept on it for 12 weeks, OK? And that's another thing that we'll come back to. This is one of the things that's been shown over and over now in the literature that if you keep these dogs on the diet that that they have responded.

Then they're actually very likely to be able to be switched back to the diet that they had before without having any clinical signs again. And that also means that very likely most of the time we're actually not dealing with food allergy, or, you know, exact food allergy in these cases. It's much more likely to be food intolerance because, you know, it doesn't come back if you challenge them.

And so that's an important fact to know as well. The next thing we, we did was if they did not respond to elimination diet, they were put on metronidazole, and if they responded within 2 weeks, they were called antibiotic responsive diarrhoea. And if both of those didn't work, food and antibiotic trial and if they needed immunosuppressive treatment to control signs, they were called SRD or steroid responsive diarrhoea.

So looking at all of that, we were going through the electronic medical records and looked at clinical activity index, age at diagnosis, and we also wanted to look at serum albumin concentration to see if there were any differences between the three groups. And what we looked at as well, which I think is really Important is outcome and we were actually interested particularly in a little bit longer term outcomes. So about a year after diagnosis, 6 months to a year and we had telephone interviews of owners and also referring vets to confirm how they were doing about a year after diagnosis.

And so what I can show you here at the time of diagnosis, In this population of sort of a secondary to tertiary referral centre at the Royal Vet College, we still had about 2/3 of dogs, 64% in the food responsive disease groups, so still a very large percentage, and we had only about 20% that needed steroids and even less, only 14% that were, antibiotic responsive. So, that's an interesting fact again because that basically confirmed. What we just said before from that older study, and I think it still holds true and tells me that, you know, a lot of times people out there will just, you know, basically disregard everybody's recommendation in private practise to really keep going with these diets because, you know, very often once I tell them, suddenly it works and so that, that's frustrating, but that's really not something that should be missed out there in clinical practise.

And the other thing that's interesting to note here is that when we were looking at the dogs that were food responsive, so just at that group, we had 131 dogs there and it was about half of them that were fed a hydrolyzed diet and half of them that were fed an elimination diet and so obviously this is retrospective, so we didn't actually have a direct comparison between these two, but what I can tell you here is that it didn't matter for outcome at all, actually. Both of those either fed with hydrolyzed or elimination diet did really, really well. We're going to be talking about the outcome in just a minute.

We had, only. Two dogs that actually had a home cooked diet, probably mostly because we used to send them to a nutritionist to get a consultation and actually get a home diet formulated. So we didn't have many owners taking that up actually, but what you can see here is that it's about 50/50 for hydrolyzin elimination diet and outcome is the same.

So what I can show you about the age in these dogs, which is definitely interesting to see is one of the things that we've talked about before is that food responsive disease dogs are are of less age or younger, than the steroid responsive disease dogs. However, if we compare the three groups, actually, interestingly, the antibiotic responsive disease one are the youngest. So that's interesting, because it's not been reported before and so maybe that's one of the things to keep in mind that potentially, you know, these dogs actually do come in fairly young.

The clinical activity index, it's the other way around actually, for food responsive disease, it was the lowest, and then it went a little bit higher up for antibiotic responsive disease. I had a median of about 8, and for steroid responsive disease, it was a medium of 9, which is, . Fairly significant disease already.

So you can see obviously over time, probably, the older the dogs get, the more severe. We also see them. And so depending on at what stage you diagnose them, I think they can fall in, in either one of these categories.

If we look at the serumalmine concentration, it's the other way around, and that again obviously makes sense. You probably have more of a leaky gut barrier and potentially more loss of your serum albumin through the gut wall. And so, with, with steroid responsive diarrhoea, you will have your albumin the lowest and then it's a little bit higher for ARD and it's the highest for, for food responsive disease.

Interesting to see. Here, if you look at the means, actually, they were all still in the normal reference range, although you can see that some of them actually did go quite low. So, that just looking at the mean, they were still in the reference range, but some dogs actually did quite get quite low, especially for the er responsive ones.

And I would say, you know, anything going lower than 1510 to 15 is obviously gonna to show clinically as a protein losing enteropathy case. So if we look at that long-term outcome and we're looking at 6 months to a year after discharge, it was really interesting to see that the outcome was significantly better for food responsive disease versus the two other groups. And so, that makes sense, of course, because they're probably also easier to treat.

However, I think it's really important to realise that all of these dogs were fed. That initial diet that they responded to for only 12 weeks and after that, they were put back on the diet that they had before and they still were doing very well about a year after diagnosis. And so I think that's a really good fact to know out there because once they respond, it's very much possible that they go back and basically are on a normal diet again without clinical signs.

So in summary, about 2/3 of dogs, even in a secondary to tertiary referral institution are food responsive disease dogs. The ARD antibiotic responsive disease dogs are the youngest, followed by food responsive dogs and then steroid responsive dogs, and it seems that food responsive disease dogs have less severe clinical signs than both of the others. And so, Those are the things that I think really help you out in practise, to come to a conclusion of how likely it is that the patient that you're seeing in front of you is likely going to be a food responsive disease case or not.

And so I think, these things can help you and try and push in that direction and say there is good data out there that the dog that you have is likely to respond to this or not. And, this is the other thing that we were talking about before, the hydrolyzed versus elimination diet, had exactly the same outcome data, so it does not seem to matter whether you take a hydrolyzed or an elimination diet. And I think these days, it's becoming more and more difficult to find specific elimination diets for the dogs that you.

Seeing, many of them will have been fed pretty much everything under the sun you can imagine, and so it can be hard to find a diet, with a protein source that they haven't had before. And so a lot of times people will now go to hydrolyzed diets and the only thing there, is in my, in my practise at least that there's some different. Differences in palatability and some hydrolyzed diets will be better taken, and that's an important fact if you want them to be kept on that diet for 12 weeks.

So, see if you can find one that the dogs will eat readily because you want them to keep going for it about 12 weeks before you switching back to the diet that they had before. So now going on to the dairy treatment, and how many dogs actually do need it. From that study in Bern, we know that we had about 13 to 2/3, so it was 1/3 of the dogs that needed prednisolone to get a clinical response from them.

And interestingly, about a third of the dogs treated with steroids did either not respond from the beginning or they experienced a relapse after treatment. So my protocol is usually that I go with 2 mix per cake, so quite a high dose for about 10 days, and then I start to slowly taper them down over another 2 to 2 to 4 months. So it's a Total period of about 6 months that they get steroids, but I do taper them fairly quickly after about 2 weeks.

But what happens a lot is that once you try and decrease that dose, they relapse. And so that's one of the concerns that we have. And so the question is what else to do with these dogs?

We're gonna be looking at some other options for you in, in just a minute. So what is it that makes the dogs not respond to long-term steroids, and this is another thing that we have a little bit of data on. And it's to do with a protein called P glycoprotein, which is a protein that's a carrier protein that basically shuffles all sorts of medications in and outside of the cell.

And it's actually the same protein that's responsible for multiple drug resistance for antimicrobial drugs as well as multiple drug resistance in chemotherapy. And so, this protein is therefore really quite important, and it's been shown that if peak glycoprotein in the duodenum of dogs with IBD is up regulated after treatment with steroids, then that's obviously associated with worse outcome. Interestingly, some dogs will actually have it up regulated before they've even seen any steroids, and so those are probably the dogs that From the beginning will not actually respond very nicely to steroids.

And so that's a concern, of course, because you won't know unless you test for it. And unfortunately, there's no test out there that will tell you from just the serum test, you, you would have to get intestinal biopsies and request that specifically. And so, that's a bit of a hassle and unfortunately not really available just yet.

However, it is the reason for failure of steroid treatment in a lot of dogs. So what are the other options for dogs who need immunosuppressive treatment? So there's a few more options out there, of course.

The Deinide is one of them and cyclosporin is another one. We're gonna be talking about these two, just a little bit to give you some information on them. So podesonide is an interesting one.

Podesonide is actually the drug that's used most commonly for inflammatory bowel disease treatment in people these days. And that's to do with, it in humans actually having an 80 to 90% 1st pass hepatic metabolism. What that means is that it's being metabolised in the liver before its metabolites are.

And going into the periphery and basically causing side effects there. And so that means that a lot of the side effects are basically suppressed, so you don't have the side effects that you usually have with prednisolone, but you have the same efficacy. And so that's kind of nice and obviously since that's the case in people, you can see why that's the first choice usually.

So the thing was of course to try and figure out whether that is a good thing to try in dogs as well. And there's now a couple of papers out there. This was the 1st 1st study that's been described, and this is from an Italian group where they've looked at 11 dogs and what they did was they treated them with podeinide.

And they looked at efficacy of treatment and they did actually have efficacy within about a month of treatment in 8 of the 11 dogs and so that sounds to me like it's about similar to what's previously been reported for efficacy in prednisolone, so it's kind of similar to that. But then what they were also interested in looking at was whether there was any influence of the drug on the hypothalamic pituitary adrenal axis, and that's because that will give you an indication that there is still enough prednisolone circulating in the peripheral blood such that you will actually have side effects from it. And what was interesting in this specific study is that they found in all of the dogs a drug accumulation within the blood within one week of treatment.

And so unfortunately, that means that the first past hepatic metabolism that you know, we were hopeful that it was, would happen in dogs as well, really isn't the case. So much in dogs and so that's probably one of the problems that we have with them. So a lot of dogs, if you try budesonide will actually still have side effects.

So that's one of the things to consider. And the other thing that's really a little bit difficult with this drug is that it comes in tablets that are in 3 milligrammes. And that's the dosage that you gave to about a 70 kilogramme human being basically.

And so that's how it was made up. The problem that we have is that we don't actually have an accurate dose as to how much we should actually give our small animal patients. And so what most people have been doing is actually Taking that dose and basically giving that one tablet, the 3 milligramme tablet per metre square for the surface area, and what you can see here, what that resulted in in these dogs because it's very difficult to give, is actually quite a wide dose range of about between 0.5 to 3 mg per cake per dog and make per dog.

I'm sorry, and so, that's the other difficulty with this drug. We're not quite sure how to dose it. It's even harder in cats, as you can imagine, of course, and it is fairly unpredictable which dogs will still have side effects or not.

Now, having said that, I do have a few dogs that have actually responded quite well to podesonide, and what I would say is that Dogs where I would consider that is the dogs that do respond to prednisolone. So I know that they're OK on steroids because they're going to be controlled on steroids. However, they have severe side effects that are intolerable, and that will be when I try it and see if if you can bring down the side effects without losing efficacy.

The other option is cyclosporin, and there's this one paper out there, where, a while ago, 2006, we looked at 14 dogs with severe steroid refractory IBD. These dogs all have had prednisolone, for a long time before they were enrolled into this clinical trial. And so at that point, the owners really were kind of at their wits end and they you know, we're just gonna be trialling this as a last resort.

So very severely affected cases, many of them also presenting as protein losing enteropathy. And what we did was we tapered off the steroids and then put them on 5 milligrammes per kilogramme orally once a day of. Was born for 10 weeks.

We also did pharmacokinetic profiles in 8 of these dogs to see if they would actually absorb it appropriately, especially if they're affected severely. It's always hard to know whether it's actually going into the blood as it should be, and we also measure clinical activity index of disease before and after treatment, as well as monitoring side effects. So what I can show you here is that the short-term efficacy, meaning over the 1st 10 weeks of that trial were really very good.

We had about 12 or 14 dogs, that went into remission and the long-term efficacy, and this is really looking at the 3-year outcome was still very, very good. At about 9 or 14 dogs that were still in complete remission, and half of these dogs actually were not on cyclosporin anymore, so they had had it discontinued after the 10 weeks of the clinical trial and so we're still in complete remission 2 years and longer after that. Also, the pharmacokinetic profile showed that the absorption, even in severely affected dogs, was similar to healthy dogs.

And so that's good because that's not a concern anymore. And the other interesting thing is that we did another endoscopy after treatment and what we found was that the T cell numbers were decreased and that's Interesting actually because even with prednisolone, that is not something we usually see after treatment if we take biopsies again. This only happens with cyclosporin, so getting rid of the lymphocytes and plasma cells that hang around in there too long and probably are causing the inflammatory changes only happens with cyclosporin.

So cyclosporin is well absorbed in severe canine IBD cases and we did have long-term efficacy in 9 or 14 cases, so it helps in some of them, you can basically save them, but it doesn't help in all. And so there is obviously still other work going on to look. Possible other treatment options.

We are right now looking at, small molecule inhibitors for IL one, which is interleukin 1 beta, and that seems to be promising for that, but, we, we are still enrolling cases, so can't tell for sure yet. Cyclosporin has side effects as we know, and unfortunately, some of them are, anorexia and vomiting, and so these sort of things, are obviously not great in IBD cases. And so I always warn my owners about these possibilities of side effects.

And if I Have them and if there's newly occurring vomiting, especially about 1 to 2 hours after giving the pill, that is about when you have the peak levels of cyclosporin appearing in the blood, that's when it, you know, that tells you that it's probably associated with the cyclosporin. And if that happens, then what I tell my owners is to basically reduce the dosage to about 5 to about 2.5 milligrammes per kilogramme for the 1st 2 weeks and then I bump it up again.

And that seems to work quite well. You can then continue for about 10 weeks, which is usually what I do, and then discontinue it. There's no need for slow tapering of this drug.

OK, now, just talking a little bit over the last few minutes about protein losing enteropathy cases. Those are of course a lot rarer to see in private practise, but we do see them and I think it's important to talk about them a little bit as well. So these are the severely affected cases where the barrier function of the, intestine is broken and we do get protein loss, unselective protein loss.

With a pan hypoproteinemia in these cases. They usually have severe small intestinal diarrhoea. They have weight loss, they can have ascitis from the low serum albumin concentration.

They can also have peripheral edoema, as you can see in this dog, that, had peripheral edoema, as well as ascites, and in that second dog down here as you can see, very severe weight loss in this case. So, another thing that's recently been described in protein losing anthropathy cases is, not just the clinical signs, but also that they seem to have hypercoagulability, similarly to dogs presenting with protein losing nephropathy where it's a, a very obvious clinical sign and most of the time they actually come in with protein losing nephropathy with arterial thrombi and, and signs from That. Now that's not the case with protein losing enteropathy, however, it is something to be aware of because one of the things that I think we are missing sometimes in these cases is that they might suddenly die from thromboembolism either in the lungs, or also in the GI tract, and because of course it's difficult to diagnose, I think it's probably one of the things that we forget about quite commonly.

So this study was interesting. This was also done at the Royal Vet College. We had 15 dogs with protein losing enteropathy and had them diagnosed with lymphoma or IBD and we performed TED, which is thrombo el elastography, which is an interesting test.

Because it gives you an assessment of the whole duration of the coagulation basically from the formation of the primary hemostasis up to coagulation factors and thrombus formation involved and then also fibrinolysis. And so when we were looking at this, we had several dogs where we had a second measurement 10 to 14 days after starting immunosuppressive treatment with prednisolone, and all of these dogs were still hypercoagulable. So, albumin and clinical activity index was improved, however, they were still very hypercoagulable at that point.

Of course. You know, we know that prednisolone particularly is also a treatment that increases coagulability that makes it hypercoagulable and so it's hard to tell at this point whether, you know, how much of that actually contributed, was contributed from the prednisolone. However, antithrombin actually wasn't really that low in these cases and so it seems like It's not the same mechanism, so it's not that you're losing too much of your anticoagulants like antithrombin II.

And so there's probably other mechanisms and we're thinking it's probably more to do with actual inflammatory reactions that are also present in the periphery, not just in the intestine in these dogs. So one of the things to potentially think about with PLE, you know, do we have to be more careful with steroid treatment? Does that push them towards that hypercoagulability state that they already have and is it potentially responsible for some of these dogs not doing well and In fact, prognosis for protein losing enteropathy cases really is still quite bad.

It's about 50/50. Either they do well within about a month, or they crash and die. And so we still, you know, for the 50% that don't do well, really don't have a good handle.

So one of the things that we're doing now actually routinely is to put these dogs on clopidogrel, which seems to be better than mini aspirins. Unfortunately, it's expensive and it also needs monitoring because if you overdo it, of course, there's gonna be bleeding tendencies, but that might be one of the things to do, especially in the very severe cases where you're afraid and, and maybe you have them on steroids anyway and you want to counteract that. So other treatment options for PLH is quickly and I think that's that's important to talk about as well.

There are reports out there, particularly in Yorkshire Terriers with so-called primary lymphangicasia. That's an interesting thing to say actually because I do think at least in my practise, usually these cases will still have a significant inflammatory component, so it will still be a secondary lymphagiatasia in Yorkshire areas most commonly. But what's important to note is that quite a lot of these dogs seem to respond well to diet.

So if you have these Yorkshire terriers walking in with ascites, maybe some small intestinal diarrhoea, but clinically, actually doing quite well, still eating, you know, still being quite well. Otherwise, those might be the ones that you want to trial on a diet first, and, important. There is actually that you take a diet that is low fat but still has enough protein in it so that they will get enough albumin to actually pump up their albumin eventually.

So high energy, low fat, high carbohydrate is usually the thing to do, needs to have a high digestibility and you can certainly look at normal protein diets, but look at your fat content there. So immunosuppressive treatment, if we're talking about protein losing enteropathy cases, again, prednisolone is of course an option but as we just said before, the success rate really is not that impressive. It's better with cyclosporin, or.

Combination of prednisolone and cyclosporin, but if you're just going with steroids, it's about fifty-fifty. So, not that impressive. And so I think, you know, thinking about your options for possible prevention of thromboembolism is definitely one of the things to do.

Other things that we haven't really talked about and are not just important for protein losing enteropathy cases, but of course for any dogs with chronic diarrhoea, are additional things like for example cobalamine, and cobalamine is a vitamin that's absorbed in the terminal ileum through receptor-mediated absorption. And it is one of these things that is very often low in chronic enteropathy, and that goes for food responsive as well as steroid responsive as well as PLE cases. So it is really important to measure it and to supplement it.

As you know with cobalamine, you can really go wrong, you just have to give it enough or as much as possible, basically, because it is a water-soluble vitamin and it will be excreted through the kidneys if you give too much of it. So, not really a risk to overdose there. Vitamin D is another one that we've recently looked at.

We've just done a study in 43 dogs with protein losing and neuropathy, and the medium vitamin D concentration in the serum was significantly lower in dogs with negative outcome versus the dogs that had a good outcome. And so again, those were about the 50/50% that everybody seems to usually see with protein losing enteropathy. Cases, so, you, you get either those that do well or those that don't.

And in the group of the dogs that really didn't do well, they had significantly low vitamin D, which is probably an absorption problem. They don't get enough that they absorb through their disease intestine, and so that's another thing to potentially consider and supplement in these cases. So in summary, does every dog need steroids?

I think that's a clear no. As we've seen, almost 2/3 of dogs in a secondary referral institution are still food responsive disease dogs. Then we have steroid responsive, diarrhoea that comprises about 20% of dogs.

And antibiotic responsive dogs only comprise about 15% of dogs. And in SRD dogs, only about 30 to 50% actually respond to steroids and so that's always something to keep in mind and think about telling that to owners up front as well so they don't get frustrated. It's important to be adamant about your diets, OK?

Elimination diet, hydrolyzed diet doesn't matter. 95% of food responsive disease dogs will respond within two weeks of starting the trial. So keep at it, and, and try and counsel your clients, that it is really worthwhile because it's curable if it's FRD and you can go and basically have them on for 12 weeks and then switch them back to the original diet and most of them will never come back.

Also, what we've seen more and more when we look back on all the cases that we've seen is that if you happen to see dogs that are less than a year old, where, you know, again, you're probably not thinking of going for endoscopy because they're just still very young, many of these dogs, if you put them on an elimination diet for long enough, 10 to 12 weeks, you can switch them back and they will never look back and not have any signs anymore. So if diet doesn't work, antibiotics and steroids will work in an additional 20% of cases. Podeinab is an option, although it's expensive, it might work.

There's an issue with dosing cause we don't know an exact dose range actually. And there's also an issue with possible side effects. Unfortunately, it's unpredictable which dogs will still have side effects from steroids.

And if owners can afford it, cyclosporin is definitely an option for some of these dogs. All right. And that concludes our webinar for today and I'm happy to take any questions.

Thank you very much. Thank you very much for that, Karen. It's absolutely fantastic talk there.

Yes, as, as Karen's mentioned, we do have some time for a Q&A session, so if you have any questions in mind, please do feel free to submit them into the Q&A box on screen. We do have some already, submitted. Karen, you'll be happy to know?

Yeah, absolutely. So firstly, a couple of, just clarifications, with a, with a few little bits and bobs here. So, firstly, someone's asking for clarification on, the letters in C C E C A I.

Yes, absolutely. So CCCAI is the Canine Chronic Enteropathy Clinical Activity Index. And it's one of the, indices that we use for objective, measurement of clinical activity, and it's been published in a paper in 2007, and I can I can send that out, if anybody's interested, and it is a good way also out in practise to try.

And have an objective measure of how severely affected your clinical patients are and it's nice to have something that you can track as well for monitoring after treatment. And I'm also pleased to say that we're probably gonna have an app hopefully out soon, which should be available at some point, so that it's gonna be easier for for practitioners and also for our students to input these sort of objective measures. Oh fantastic.

OK, so, yes, what we can do then if you send us that information after the webinar, we'll make sure it's in the comments, for the recording so people can find that easily. And when the app goes live as well, we'll be happy to, distribute that, and let know. OK, so in some more, meaty clinical questions.

So we'll start with, how do you, how would you get a dog with GI disease and a poor appetite to actually eat the exclusion or? Hydro hydrolyzed diet in the first place. Yes, that's a very good question, and that can be very tricky, of course, and I would say, you know, once you have a dog that's already anorexic, that is definitely one of the things that's, that's difficult to deal with.

And I would say, I'm probably in a little bit of a privileged situation because I Usually have owners that want to go all the way and they're really in it for everything. But some of these dogs specifically in the beginning might actually need some help with feeding tube placement. And what I frequently do is actually esophageal tooth placement even in larger breed dogs because it just helps to supplement them.

While we're waiting for the immunosuppressives to kick in, and that can be, especially important for drugs like cyclosporin that might actually suppress appetite in the beginning as well. And it also takes cyclosporin about 10 days before it actually works. And so, to give them that sort of support in the 1st 10 days can be really important and so that's what I usually do then.

Brilliant, thank you for that. And just sticking with the diet theme for the time being, Lisa's asked which hydrolysed diets do you recommend? Yes, absolutely, with hydrolyzed diets.

So, there's obviously more or less palatable hydrolyzed diets out there, and, one of the diets that I use very often is the Purina HA diet. I've also done several clinical trials with that diet, particularly because it's a diet that is, is Fairly palatable and, and dogs will eat it for a long time. The, feather hydrolyzed diet, by Royal Canyon is another one that actually seems to work quite well, I think, and so that's another one that you can trial, of course.

So those are the ones that I usually trial with these dogs. Fantastic. Thank you.

So we have a few questions here, . sorry, regarding, the clopidogrel. Yeah, so how, what do you recommend for monitoring it?

So we have PT, PTT, BM, PT, there's lots of questions coming in about that. Yes, absolutely. So, for clopidogrel, what I usually go for, is 2 milligrammes per kilogramme orally once a day, and you can bump that up to 4 milligrammes per kilogramme, but I usually go with the.

Low dose of 2 makes per cake. The bleeding complications with that dose are not usually as severe as you see them with the, with the higher dose. That's also why I do the 2 makes per cake.

If you want to, want to monitor, you can do either of those. You can do PT, PTT, or you can do B mucosal bleeding times. I find with the B mucosal bleeding.

It depends a little bit on the dogs. Some of them will be very squirmish and, and it's gonna be difficult to, to do serial assessments, especially if you've done it a couple of times and they know what you're gonna do. So, you're gonna have to find out how, how well they do basically with that.

PT PTT is of course, you know, the, the standard test, and the gold standard, so that should work fine. Perfect, thank you. Lots and lots of questions and comments still coming in.

Zara says thanks, best webinar I've watched in a while, very useful info and at the right depth of detail. Oh great, glad to hear that coming back. A lot of questions coming in, regarding, probiotics.

Yes, of course. Yes. So probiotics and it's true, I've actually kind of said that I was gonna go into that.

And so probiotics, is a little bit of a, of a dilemma because there's, only, data out there for the efficacy of probiotics in our small animal patients, for acute diarrhoea. OK? So what I would say if you're out there in clinical practise and you see your acute diarrhoea cases, which I'm sure you see a lot, you know, try and, and do.

Not reach for antibiotics if you can and, and give probiotics instead. There is some evidence, it's not particularly strong yet, but it's there that it will work and it probably works better than antibiotics and of course now that we know that we really shouldn't be giving so many antibiotics, especially indiscriminately and we don't know what we're treating like in acute diarrhoea cases. I think that's probably where the most indicated.

So if we go into chronic diarrhoea, unfortunately, the evidence is really scarce and so now we're talking about enterococcus fuium probably products and maybe VSL number 3 products. Those are probably the ones that have been studied most, and unfortunately there's no evidence that they have any efficacy in. In long term chronic diarrhoea cases.

Now, that doesn't mean that it's wrong to give it. Of course, we know that they don't have side effects and they might very well have subtle effects on the immune system in the GI tract and also the microbiome. And so it's probably not wrong to give, but unfortunately, there's not much evidence that they, at least by themselves really do that much.

OK, great. Thank you very much. .

We, we've sort of hit the time limit now. Are you OK to stick around for a few more minutes to answer a few questions? OK.

Yeah, absolutely. Wonderful. I mean, we, we're not, unfortunately everyone gonna be able to get through all of them because there are lots coming in, but we will send, we will send everyone's questions across to sponsors and the speakers to see if we can get some .

Perhaps more information or or where to find some information perhaps a lot of positive information and feedback coming in as well. I had an interesting question, where is that gone? Talking about, if cyclosporin, is sorry, I've lost it.

Where's that gone? Sorry, apologies for this, there are lots of questions coming in at the moment. Mm mm mm.

I To find it. OK, no problem. There's an interesting question, regarding the, faecal treatments.

I'm not sure if you've seen this. No. Oh I've lost that as well now, apologies about this, there are lots of questions still flying in.

That faecal transplantation. Yes, that's exactly it. So someone was mentioning there's a lot of talk about it at the moment.

Yeah, there's a lot of talk about it, absolutely. So, faecal transplantation is one of the things that has come up recently, absolutely, and, again, there isn't really that much evidence out there yet. One of the things that seems to come up with some of the The things that have been done from the University of Texas with Jan Zukowski as as a main author is that it seems to work for a little bit as in what happens is basically that you restore the microbiome for a short amount of time and if you happen to actually look at the microbiome, you will see that it switches to the Microbiome of the donor, once you've given the faecal transplant, then that kind of makes sense.

So you basically exchange it completely and that then gets rid of the clinical signs for a little while and it's usually not for longer than a few weeks. And then after that, it, the signs come back, usually for inflammatory bowel disease at least, and that's at the most that's been studied in in dogs so far. And then you're gonna have to repeat the treatment and so it seems like it does something in the short term, but it doesn't seem to manifest, long enough, sort of a, a treatment duration.

OK, great, thank you very much for that. A few questions coming in, in regards to the carbalamine, supplementation as well. What are your thoughts on, oral versus injectable, good question.

So there's a lot of talk now about oral cobalamine supplementation and of course, you know, thinking about the whole receptor mediated absorption, it kind of doesn't make sense that you can give it orally because, you know, if the are gone in the ileum, then why would it work? But it's actually been known for decades in human medicine that you can give oral cobalamine if you give it in high enough doses, what will happen is basically that it goes paracellularly between the cells and will still be absorbed. Now, the thing that you have to realise if you do that is that you have to give massive doses, you have to give a lot more than subcutaneously and you have to give it daily.

And it's kind of similar to probiotics. It's, the day that you're not giving it anymore, there will not be a longer effect from that. So it's not like a subcutaneous injection that will last you for a few weeks.

If you really have to give it every day and the moment you discontinue it, you won't have any effect anymore. So, but it is a possibility and I would say I've had several cats, where That was actually much better tolerated than the subcutaneous injections because as you all know, it's it's actually stings when you get it subcutaneously and that that can be a pain, you know, for the owners as well as for, for the animals. And so that's, that's certainly an option and it seems like, you know, for, for a lot of, of animals, that's potentially a better option than giving the subcutaneous treatments.

OK, fantastic. Thank you very much. A couple of questions just finally, on, the order of treatments.

So for example, cyclosporin. If, if you're concerned about the hypercoagulable state, of any PLE cases, would you consider bypassing the prednisolone, prescribing cyclosporin, or you, sorry, apologies for my, pronunciation there first. Yeah.

So, I, I, I guess it depends a bit what kind of cases you see. Usually see the cases that that have failed a lot of other treatments and most of the time they will have been on, on prednisolone before and you know, if I know that they have failed it, then obviously I'm not going to put them on again because it's not working and also because I'm concerned about side effects and hypercoagulability and so in these cases, I will go to cyclosporin. Direct, having said that, a lot of these cases will need additional support, like, for example, an esophageal tube placement, to support them through the first two weeks because they won't eat, maybe they will, you know, get even more anorexic and start vomiting on the cyclosporin and so these things need addressing, definitely.

And, but, but I would say it's, it depends what cases you see. So if they haven't had prednisolone before, what I also often do is actually put them on prednisolone and cyclosporin at the same time. And then try and taper down the excuse me, the prednisolone fairly quickly.

So then, I use the cyclosporin as a steroid sparing agent, and so I basically give it so that I can decrease the prednisolone in the, after about 10 to 14 days. And obviously the the advantage of that is also that, you know, hopefully with the side effects of prednisolone and it acting fairly quickly within about two days or so, you should see those animals starting to eat as well. And so that's, that's definitely another thing that you can try.

OK, perfect. And just touching on the prednisolone there, should dogs on prednisolone be given preventative, anti-ulcer treatments? So, if, if it's just prednisolone, then I'm actually not usually worried about GI alteration.

When I get worried, is of course, if, if they're also on non-steroidal in inflammatory drugs, which of course, you know, some middle aged to older dogs will be because of arthritis and other treatments. They're on basically and then you definitely have to be very careful, absolutely. And if you wanna give them, let's say, something like an anti-ulcer treatment that's definitely indicated in these cases, or if you can, best would probably be to try and, and reduce or discontinue the NSAIDs if possible.

OK, great. If you were monitoring, serum cyclosporin, is there a correct time post dosing to check efficacy, very good question. So yes, if you, if you, so the problem with cyclosporin measurements is that there is no correlation with efficacy, OK?

So if you want to find out that the cyclosporin works in your case, then you're gonna have to watch it clinically. The serum cyclosporin level is not gonna help you with that because it doesn't correlate. What it will help you with, if You want to check for that is whether you have a very high absorption rate in a case, which means that it's one of these cases where you get a very high peak level.

And what happens in these cases is that within an hour or two after giving the pill, they will have very high serum levels and it's above 750 nanograms per millilitres and if it's higher than that. Then that tells you that this is one of the dogs that for some reason absorbs it very, very, efficiently and basically has too high a level in the blood and that can make you sick, not eating and vomiting. And so if that's the case, then you can reduce it.

But then again, it might not be necessary because you can suspect that that's what's happening from your clinical presentation, as in when they You know, reports that they have newly developed vomiting about 1 to 2 hours after giving the pill. There's no use of measuring cyclosporin later than that, later than 1 to 2 hours after giving the pill because the peak level will drop off very quickly in the blood and the level 24 hours after is almost 0. So there's no use in measuring it later than that.

OK, fantastic. Thank you very much. A couple of people asking about, azathioprine, prone, sorry, is steroid sparing for IBD.

Is that something you have, yes, yes. So azathioprine, absolutely is another one that, another immunosuppressive that a lot of people use as, as a steroids-bearing agent. It's obviously cheaper than cyclosporin.

The problem I have with azathioprine is other side effects, of course, that you get with that, you know, including hepatotoxicity and also bone marrow toxic. And so, I don't like it for these reasons, but then of course, you know, it might be one of the things to consider. The other problem is azathioprine is of course that it takes even longer than cyclosporin to actually have an effect and so it takes about 3 weeks until you can start to think about discontinuing your prednisolone and that's another reason why I don't usually use that.

OK, that's fantastic. Great information. Thank you.

Just finally then, we'll touch on a couple of people asking, about, when in your investigation would you do an endoscopy or a bowel biopsy? Would you mind just going through quickly, how, how you'd usually go about your investigation? Yeah, I guess we've talked about this just a little bit in the beginning about the World Cup and when to do an endoscopy.

So I think with all the information that we have out there now, specifically related to food responsive diarrhoea, I think it is really important to try and nail down, whether you have a case of food responsive diarrhoea in front of you. There's no use of doing an endoscopy in these cases, obviously, and you know. I would say that I am fairly often get cases referred where people are very set on coming to do an endoscopy because I'm the last person they see and they, you know, they just want to go for the procedure.

But if they haven't had, you know, a diet trial that, you know, has, has excluded food responsive diarrhoea, I will tell them that we can do endoscopy, but they will still go home on a diet. And so that's, that's the thing, you know, that they need to realise basically. And so I, I'm quite adamant by now to, you know, not basically try and, and, and get biopsies on these cases.

Yeah, that makes sense. Fantastic. Karen, I'm sure we could listen to you all night long, but, we've, we've run over already and so thank you very much, for staying on for us and answering as many questions as possible.

Sure, not a problem. It was a lot of fun things. Yeah, it's brilliant talk, for everyone listening in the recording will be out on the website, within the next couple of days, so stay tuned if there's anything you missed or you want to cover again, cos there's a lot of information in there.

It will be up shortly. Thanks once again to Purina for sponsoring this webinar and making it free to everyone tonight, and thank you again, Karen for an amazing talk. Yeah, no problem.

Thank you. Thanks, everyone. Good night.