Good evening everybody, and welcome to a Thursday night members webinar. My name is Bruce Stevenson, and it is my privilege to be chairing tonight's session. I don't think we've got any new people in, so the usual rules apply.

Questions into the Q&A box, and we will hold those over to the end. So tonight's presenter is no stranger to us. Miles McKenna graduated from the University College in Dublin in 2013.

After some time in general practise, he completed an internship in small animal medicine and surgery at Cornell University in the United States. He subsequently undertook a master's of Veterinary Science at the University of Edinburgh, and in 2019, he completed a residency in small animal internal medicine and a master's of Veterinary Medicine at the Royal Veterinary College. Thus becoming a diplomat of the American and European Colleges of Veterinary Internal Medicine.

Since completing his residency, he has worked mainly in private referral practise in the UK, but now Miles is assistant professor of internal medicine at UCD in Dublin. Miles, welcome back to the webinar, vet and over to you. Thanks very much for the introduction, Bruce, and welcome everybody to this webinar on how to approach difficult cases of canine inflammatory bowel disease.

So in this webinar, I'll start with a brief overview of the pathophysiology and classifications of chronic enteropathies, including inflammatory bowel disease in dogs. We'll then move on to discuss the general approach that should be taken to work up a case of chronic diarrhoea or vomiting and the standard treatments for chronic enteropathies that are commonly employed. And finally then we'll discuss troubleshooting those difficult cases of inflammatory bowel disease that don't seem to respond to treatment as expected for those patients who seem to experience frequent recurrence of their clinical assigns.

So, chronic enteropathies are the most common cause of chronic diarrhoea and vomiting in dogs. Chronic here means that the clinical signs have been ongoing for at least 3 weeks, and enteropathy meaning that these are primary diseases affecting the gastrointestinal tract. To reach a diagnosis of a chronic enteropathy, it's first of all necessary to rule out any other cause of chronic diarrhoea or vomiting, including extra gastrointestinal diseases and other primary gastrointestinal diseases.

And ideally also by documenting evidence of inflammation on histopathology of biopsies taken from the gastrointestinal tract. The term chronic enteropathy is really an umbrella term, and it's used to cover various subcategories of inflammatory diseases of the gastrointestinal tract. So there are 3 main subclasses of chronic enteropathy, the first being food responsive enteropathy, the second being antibiotic responsive enteropathy, and the third being inflammatory bowel disease or IBD for short.

Now, the term inflammatory bowel disease is often used interchangeably with the term chronic enteropathy. And so many patients with chronic enteropathy do in fact have IBD. But technically inflammatory bowel disease is actually a subcategory of the wider umbrella term of chronic enteropathy, and we'll discuss this a little bit more in subsequent slides.

As to what causes these chronic enteropathies, including inflammatory bowel disease, unfortunately there's no simple answer to this. The old line of thinking was that chronic enteropathies were idiopathic inflammatory diseases with no detectable underlying cause. But in recent times we've come to realise that the pathogenesis of chronic enteropathies.

Is actually a very complex interplay of several different factors that may include an individual dog's genetics, changes in an individual's immune response in the gut, some environmental triggers such as dietary factors, and the host microbiome. So there seem to be several factors at play at play, but in reality the cause of it is still really idiopathic in that it often it's a combination of many of these different causes and we generally can't pinpoint any one discrete cause in an individual patient. To understand the pathogenesis of how chronic enteropathies, including inflammatory bowel disease work, let's first of all look at how the healthy gut works.

So the healthy gut manages to distinguish pathogenic microbes from harmless micro flow. In the gut and can initiate controlled immune responses to deal with pathogens while maintaining a hypo responsiveness to commensal bacteria in the gut. And it's this hypo responsiveness, which we term immune tolerance.

This discriminatory process of distinguishing harmless from harmful microbes is mediated by specific receptors in the gut called pattern recognition receptors. And these receptors are expressed on both epithelial cells in the gut and non-epithelial cells like macrophages and dendritic cells in the gut wall. So antigens of commensal bacteria are detected by specific pattern recognition receptors in the gut and are then presented to antigen presenting by antigen presenting cells to T lymphocytes, which differentiate into specialised cells called Tregulatory cells.

And these cells mediate immune. To commensal microbes by secreting anti-inflammatory cytokines like interleukin 10 and TGF beta. So, this, complex interaction of commensal microflora with the pattern recognition receptors ensures that the healthy gut doesn't have an abnormal inflammatory response to harmless organisms.

On the other hand, in patients with chronic enteropathies like inflammatory bowel disease, pathology occurs when this normal immune tolerance is lost. We don't yet know exactly why these patients lose immune tolerance, but as mentioned in a previous slide, it's likely influenced by several factors such as genetics, diet, and the microenvironment in the gut. The loss of immune tolerance leads to an abnormal inflammatory response to normal, normally harmless antigens in the gut lumen, such as commensal bacteria or even dietary proteins, and this in turn causes the chronic inflammation that is characteristic of chronic enteropathies like inflammatory bowel disease.

The chronic inflammation can eventually cause damage to the gut wall, and this exacerbates the loss of immune tolerance even further. So normal gut immune tolerance relies on the existence of an intact mucosal barrier in the gastrointestinal tract, but if. The normal mucosal barrier is damaged by chronic inflammation, then microbes can invade the mucosa of the gastrointestinal tract.

And this results in the production of more pro-inflammatory cytokines, which causes worsening inflammation and this becomes a really vicious cycle. The the loss of immune tolerance and altered function of the mucosal barrier in the intestines may lead to an intolerance to luminal components like dietary nutrients and luminal bacteria, and that really characterises the pathology that we see in chronic enteropathies like inflammatory bowel disease. As I mentioned a little while ago, chronic enteropathies can be classified based on the response to treatment.

So some dogs with chronic enteropathy have food responsive disease, which is where their clinical signs of vomiting or diarrhoea can be successfully managed with dietary therapy alone, and no specific medications are required in those patients. Another subset of patients have what we term antibiotic responsive enteropathy, where antibiotic therapy appears to cause a resolution of their clinical signs. And the final group of patients with chronic enteropathy requires steroids or other immunosuppressive treatments to control their signs.

And it's these patients who are most severely affected and who require immunosuppressive treatments to control their signs, who we consider to have true inflammatory bowel disease. To touch upon each of these categories one by one in a little bit more detail, food responsive enteropathy is where patients have an abnormal inflammatory response to certain components of their diet, and typically it's the protein component of the diet that patients react badly to. With food responsive enteropathies, we see that patients tend to develop this abnormal inflammatory response to diet in the first few years of life.

So if we see signs of a chronic enteropathy in a patient who's 1 or 2 years old. You should be highly suspicious that it's likely to be food responsive. Whereas in older patients, although we can still see food responsive enteropathy, it's more likely to be one of the other categories such as antibiotic responsive enteropathy or inflammatory bowel disease.

The inflammatory response to dietary components we see in this disease can be either a type 1 hypersensitivity reaction, which is mediated by immunoglobulin E, or it can be a type 4 reaction which is a cell-mediated immune response, and some patients will have a mixture of a type 1 and type 4 hypersensitivity response to dietary protein. We can generally manage these food responsive enteropathies with dietary therapy alone, and typically the patients don't require any medications. The type of diet we give these patients is usually one of two things, either a novel protein diet, where we give the patient an unusual protein source to which they have not previously been exposed, and this protein source should be the sole protein source in that patient's diet.

The second type of diet we try in these patients is what we term a hydrolyzed protein diet, where the protein particles are broken up into very tiny pieces that are so small that the dog's immune system does not detect them as they pass through the gut. Hill's DD varieties are probably the most commonly used novel protein diets we encounter in practise, while some examples of commonly commonly used novel protein diets would include Hill's ZD, Royal Cannon hypoallergenic, and also Purina HA hypoallergenic. Now it's really important to stress that in order for dietary therapy to work in patients with food responsive enteropathies.

The prescription diet needs to be absolutely the only protein source that these dogs are offered during the course of their diet trial. So even giving a small treat or as little as a flavoured worming tablet could really undo the good of the diet trial, as this small amount of protein in that treat or flavoured tablet can trigger the inflammatory response we are aiming to avoid. It's also really important that patients receive an adequate length of a diet trial to determine if their chronic enteropathy is food responsive.

So, most dogs with food responsive enteropathy will start to show an improvement in their clinical signs within the 1st 2 weeks of initiating a new diet, but I typically advise completing a diet trial of at least 4 weeks before we conclude whether or not the patient is having a positive response to diet. It's also quite common for clients to ask if it's appropriate to use a home cooked diet in these cases. And the general answer to this is that yes, in some cases this is possible, but generally I try and talk clients out of this unless they're willing to see a specialist nutritionist about their dog's diet.

And this is because the diet needs to be very, very carefully designed to ensure it actually is a proper hypoallergenic diet. And also it's extremely difficult to avoid patients on home cooked diets developing vitamin or mineral deficiencies. So commonly patients who are going to be on long term home cooked diets.

Require an individually formulated mineral or vitamin supplement from a nutritionist long term. So for obvious reasons, it's a lot simpler to just try and feed these patients a prescription diet that is specifically formulated for dogs with food responsive enteropathies, and so only if clients are really pushing for home cooked diets, would I ever consider that. The second category of chronic enteropathy is the antibiotic responsive enteropathy, where, as the name suggests, patients experience significant improvement in their clinical signs following initiation of antibiotic therapy.

We think that many patients develop this form of chronic enteropathy because they have an underlying food responsive enteropathy that triggers abnormal inflammation in the gut, and eventually leads to mucosal damage and fat malabsorption, which leads to a major change in the intestinal microbiome. So we get overgrowth of certain bacterial species that shouldn't normally be there. And this can lead to a very severe worsening of clinical signs like diarrhoea, bloating, or abdominal discomfort.

The kind of poster child breed for this form of enteropathy is the German shepherd breed, where the enteropathy is thought to be linked to a deficiency in immunoglobulin A, which is the form of immunoglobulin that is important for immunity on mucosal surfaces like the gut. We typically will use antibiotics like metronidazole or Tylain, which are very good for treating gut bacteria, and we typically will administer the antibiotic course for approximately 3 to 4 weeks, while also continuing the dogs on a novel protein or hydrolyzed protein diet. And by the end of that 3 to 4 week course, we evaluate the patient's clinical signs again.

If they have experienced a major improvement in their clinical signs, we can conclude they have an antibiotic responsive enteropathy. But if we're still failing to see improvement, despite antibiotics and despite the hydrolyzed or novel protein diet, then we can conclude that the patient likely has true inflammatory bowel disease, where immunosuppressive therapy is needed. So, as I mentioned, the final category is true inflammatory bowel disease, where we need immunosuppressive therapy in addition to dietary therapy to control the patient's clinical signs.

Most commonly we will use an immunosuppressive dose of prednisolone as the first line therapy in these patients to help control their signs, although in some cases adding a second immunosuppressive drug like cyclosporin or azathioprine is considered. Dogs with suspected chronic enteropathies will typically present with clinical signs like chronic vomiting, chronic diarrhoea, failure to thrive, or weight loss. And the initial diagnostic workup in these patients should involve ruling out extra gastrointestinal diseases that can cause chronic diarrhoea or vomiting, and also ruling out simple problems to address like gastrointestinal parasites.

So I typically recommend that all patients presenting with chronic vomiting or diarrhoea, that is patients where these signs have been ongoing for at least 3 weeks, have haematology and biochemistry checked, have their serum folate and cobalamine checked to screen for gastrointestinal malabsorption, and I will also run an ACTH stimulation test in these patients to rule in or out Addison's disease. I also will always perform a faecal flotation to screen for gastrointestinal nematodes and also ajaria Alisa if diarrhoea is one of the presenting clinical signs. If the patient is presenting with vomiting as a clinical sign, I will also always perform a canine specific pancreatic lipase or CPLI to screen for pancreatitis.

And if the patient is exhibiting small intestinal diarrhoea, that is large amounts of diarrhoea, without any of the large intestinal signs like tensmus or fresh blood in the faeces, I will typically also perform a TLI to rule out exocrine pancreatic insufficiency. Ideally, if it's available, I would also always recommend performing abdominal ultrasound in patients presenting with chronic chronic vomiting or diarrhoea. This is gonna be a lot more sensitive than just taking an abdominal radiograph to look for abnormalities in the abdomen.

And we can detect many things using ultrasound, so we can use it to assess the size of the adrenal glands and to. Again, screen further for Addison's disease. We can check for ultrasonographic signs of pancreatitis in the vomiting patients, but we can also use ultrasound to image the GI tract itself.

So for example, we may find something like an intermittently obstructing gastrointestinal foreign body that could be causing the clinical signs or a focal mass within the gastrointestinal tract. Now in chronic enteropathy cases like inflammatory bowel disease. Abdominal ultrasound is usually completely unremarkable in these patients because this is a disease that is occurring on a microscopic level in the gut, rather than causing macroscopic disease that can be detected via imaging.

So we're not expecting to make a diagnosis of chronic enteropathy using ultrasound, but we are using it to rule out as many of the other causes of chronic vomiting and diarrhoea as we can. Assuming this initial diagnostic workup for chronic vomiting and diarrhoea doesn't reveal a cause of the clinical signs, then this by exclusion is consistent with a chronic enteropathy. And so at this stage, we can conclude that the patient has a chronic enteropathy, but we don't yet know which subcategory of chronic enteropathy the patient has.

So do they have food responsive, antibiotic responsive, or immunosuppressive responsive enteropathy? Now if the patient is stable, so if they have mild to moderate clinical signs, as long as they're still eating and drinking, and as long as they don't have a severe hypoprotemia on their bloods, then typically it, it's fine to take a stepwise approach to working up these. Patients.

So I typically will start with a strict diet trial with hydrolyzed or novel protein diet for at least 4 weeks, as well as supplementing the patients with cobalamine if they were found to be hypocobalaminemic on our initial bloods. If that diet trial is successful, then we conclude the patient has food responsive enteropathy, and we should consider keeping that patient on the successful diet for at least several months, if not lifelong, to maintain control of their disease. If the clinical signs don't significantly improve with diet, then the next step is to continue the diet, but to add in a 3 to 4 week course of an appropriate antibiotic like metronidazole or Tylacin.

And again, if the antibiotics successfully resolve the clinical signs, then generally what I'll do longer term in those patients is maintain them on the appropriate diet long term. But it's likely that they will need intermittent courses of antibiotics long term when they experience an exacerbation of their clinical signs. So I don't like to keep the patients on antibiotics lifelong.

That's not a good idea because we're going to encourage resistance and they're going to lose effectiveness. But these patients can need kind of pulse therapy of antibiotics during their lifetime. When they experience a sudden worsening of signs, and certainly keeping the patients on a hydrolyzed or novel protein diet long term seems to help decrease the frequency of when we need to give those patients a course of antibiotic treatment.

Now those patients failing dietary and antibiotic therapy will require immunosuppression, but it's really important that we try to obtain biopsies of the gastrointestinal tract before we initiate steroids. And this is firstly because once we initiate steroids or other immunosuppressants for that matter, it may. It may not be possible to obtain a definitive diagnosis, as histopathological changes could occur after we start the immunosuppressive therapy and so we may never reach a diagnosis.

And another reason why it's really important to collect biopsies prior to starting immunosuppressives is that other chronic gastrointestinal diseases like gastrointestinal. Lymphoma or lymphaectasia can mimic the presentation of chronic enteropathies, and we would treat these types of diseases quite differently. So we want to be sure that we're doing the right thing by these patients, treating them with immunosuppressives, and therefore, it's really important to get a biopsy, confirmed diagnosis prior to starting that therapy.

Now, in patients who have more severe clinical signs or so, you know, if they're anorexic, if they have profound diarrhoea, or if they have hypoproteinemia on their biochemistry, then generally I will proceed with gastrointestinal biopsies pretty much straight away at the time of initial presentation. Because we don't really have the luxury of trialling that patient on diet or antibiotics for several weeks, as patients with more severe disease typically will need immunosuppressive treatment in addition to dietary therapy or antibiotic therapy to control their signs. So severe.

Signs or hypoproteonemia on your bloods is an indication that you should pursue, gastrointestinal biopsies, quite early on, in the, in the diagnostic investigation rather than waiting several weeks to assess the response to diet or antibiotics. When you're at the stage in your investigations of wanting to obtain biopsies of the gastrointestinal tracts, the first question you need to ask is, what is the best way to get biopsies in that patient? Is it via surgical biopsies or via endoscopic biopsies?

In general, unless there is a really strong indication to take surgical biopsies, and I'll discuss these surgical indications, we usually prefer endoscopic biopsies because they have a significantly shorter recovery time. So patients, you know, often can go home the same day after having endoscopy when compared to surgery. And also because the risk of serious complications like developing post-procedural septic peritonitis is much lower with endoscopic biopsies compared to surgery.

So depending on the source you read, the risk of septic peritonitis after any type of enterotomy in a dog is somewhere between 8 and 15%. Whereas with endoscopic biopsies off the GI tract, it's much less than 1%, so there's a very significant difference there, and we generally consider endoscopy a lot safer and a lot less invasive. An additional benefit of endoscopy is that we can actually visualise the inside lumen of the gastrointestinal tract.

And so endoscopy can be helpful for detecting some small intrauminal masses that we could miss on ultrasound or also looking for ulceration which we may not see during exploratory laparotomy. There are, however, specific scenarios where surgical biopsies should be obtained in preference to endoscopic ones. One of these situations is if we see changes on ultrasound that indicates that the disease process and the changes on ultrasound are only present in the jujunum.

So we're usually able to access as far distally as the duodenum when we're performing an upper gastrointestinal endoscopy. And we're able to reach as far approximately as the ilium when we perform a lower gastrointestinal endoscopy. But we're not able to successfully visualise or take biopsies of the jujunum when we perform endoscopy.

So, if, for example, the ultrasound we see that there is a mass or significant changes in the jujunum, and the rest of the gastrointestinal tract looks OK, then we should get surgical biopsies in that patient because otherwise we may completely miss the diagnosis. Endoscopic biopsies are also a lot smaller and more superficial than surgical biopsies, and typically endoscopic biopsies will only capture samples of the mucosa and submucosa. And so sometimes an ultrasound we'll see that there are marked changes in the deeper layers of the gut wall, so particularly the muscular.

Layer. And if we see changes like this, so just say a patient has a very thick and muscularis layer off their gut on ultrasound, we'll typically try to get surgical biopsies in that patient because if we just perform endoscopic biopsies, we may completely miss the diagnosis because we're only going to get samples from the mucosa and submucosa. If we do decide to do endoscopic biopsies, another important consideration is to think about whether we need to perform an upper gastrointestinal endoscopy, a lower gastrointestinal endoscopy, or both.

And this decision should be made based on the dog's folate. And cobalament status and also on their presenting clinical signs. So if we find that a patient has low folate, this indicates malabsorption from the duodenum and therefore indicates we need to perform an upper gastrointestinal endoscopy to take biopsies from the duodenum.

Whereas if we see that a patient has low cobalamine, this indicates malabsorption in the ilium and indicates we should be performing a lower gastrointestinal endoscopy because this is the route by which we'll be able to access the ilium. And obviously, if both folate and cobalamine are low, then we will try and do both an upper and lower GI scope. Regarding clinical signs, if vomiting is the only clinical sign the patients are showing, then an upper gastrointestinal endoscopy might be sufficient.

And if large intestinal diarrhoea, like signs of tensmus, fresh blood in the faeces and straining is the only clinical sign, then it's probably s. To only perform a lower gastro gastrointestinal endoscopy. But if there are mixed signs, as is the case in most patients, then I typically recommend performing both an upper and lower gastrointestinal endoscopy so we can maximise the diagnostic yield of the procedure.

When we get the histopathology results of our surgical or endoscopic biopsies back from the pathologists, what we're looking to see and expecting to see in these cases are changes consistent with chronic inflammation. And importantly, we're also aiming to rule out other important differential diagnoses like lymphaectasia or lymphoma, which would necessitate a very different treatment than inflammatory bowel disease. Assuming we don't find any evidence of these other diseases like lymphoma or lymphangectasia, then in the patient with inflammatory bowel disease, we're going to want to initiate prednisolone therapy in most cases as the first line immunosuppressive treatment.

And because inflammatory bowel disease is an immune mediated disease, it's really important that we start prednisolone at a true immunosuppressive dose rather than an anti-inflammatory dose, because this is going to give us the best chance of getting the disease into remission. And an anti-inflammatory dose just may not cut it. So remember that in dogs, the immunosuppressive dose of prednisolone is between 1 and 2 milligramme per kilogramme, and typically I start these dogs on a high immunosuppressive dose because we really want to tackle the inflammation quite aggressively initially to get the disease into remission.

So I typically will start these patients on 2 milligrammes per kilogramme of prednisolone once a day. The goal is to obtain resolution of the clinical signs and once this has been achieved, the dose of prednisolone can be gradually tapered by around 25% every two weeks or so to the lowest effective dose. In some dogs, it will eventually be possible to completely discontinue prednisolone, and this is the case in most patients, but in some dogs, we will need to keep them on a low dose of daily prednisolone in the long term to help keep their disease under control.

There are some cases where prednisolone therapy might be contraindicated. So for example, dogs with hyperadrenal corticism or dogs with poorly controlled diabetes mellitus, we really want to try and avoid having those patients on high doses of steroids, so we don't upset control of their other disease. And so in these.

We will consider using an alternative immunosuppressive agent such as chlorambucil or cyclosporin, which again, the ultimate aim will be to eventually taper the dog off that immunosuppressive drug over a long period of time, while assessing that the patient's clinical signs remain under control. So what what I've been discussing in the previous slides is what I typically do to initially work up the patient with chronic vomiting and diarrhoea. And then how I tend to approach a case of chronic enteropathy and you know, rule, rule out food responsive, antibiotic responsive disease and then go on to treat their inflammatory bowel disease.

And this general approach will be. Successful in most patients, the vast majority of patients, and typically I will use this approach in the majority of dogs presenting with these signs. But I'm sure that most of you, like me, have come across some cases that just don't seem to follow the rules or respond to treatment as expected.

So you're doing everything right, you have the patient on an appropriate diet, you have them on an immunosuppressive dose of. Prednisolone, but they still are having extreme diarrhoea, extreme vomiting, and the disease just does not seem to be under control as we would expect it to be. So what I would like to discuss for the remainder of the webinar is why these patients may not be responding to treatment as expected, and how to actually approach troubleshooting these cases to try and get control of the disease.

There are lots of different reasons why a patient may not be responding to treatment as expected, so in some cases we might have an incorrect diagnosis, and that's something very important to consider. In other cases, a complication of therapy may have occurred. For example, changes in the intestinal microbiome might have occurred if patients have been on long courses of antibiotics or patients may have picked up a gastrointestinal parasite or have difficulty clearing that parasite due to being on long-term immunosuppressive therapy.

It also appears that there is a really significant individual variation in the response to immunosuppressive treatment. And this might be because some animals just suffer from a more aggressive form of the disease than others, but it's also possible the different responses to treatment could reflect individual variations. In the expression of receptors for steroids or receptors for other immunosuppressives at a cellular cellular level in those patients.

So some patients may have lots of receptors for steroids, other patients may have decreased expression of those, and that could impact an individual's response to these therapies. And these individual variations are quite poorly understood at present, but they may explain why some cases do appear to be seemingly refractory to routine treatment, while other cases will respond in a textbook fashion. So over the coming slides, I'm going to discuss 10 different things you can do to troubleshoot these difficult cases of inflammatory bowel disease that aren't responding to standard treatment.

And the first step I always take is to double check that my diagnosis is correct. So what I'll do in these patients is review the previous blood results and think about what tests I've done. So I want to ensure I haven't missed a simple diagnosis.

Like exocrine pancreatic insufficiency in a dog with diarrhoea, for example. I'll also consider the possibility that perhaps my biopsies of the gastrointestinal tract were not of sufficient quality, especially if I've taken endoscopic biopsies. So perhaps the area I biopsied wasn't correct.

For instance, maybe I only did an upper gastrointestinal endoscopy, whereas I should have maybe biopsied further down the gastrointestinal tract if cobalamin was low, for example. Or perhaps the areas of the gut I biopsied were correct, but the quality of my samples were not adequate and maybe I've missed the diagnosis. And so reviewing the histopathology report is really worthwhile in this situation to see if the pathologist has commented on the quality of your samples.

Even if you are confident that your biopsy samples were of good quality and the pathologist confirms that in the report, you should also consider the possibility that the disease the patient was initially diagnosed with might have actually transformed into something else since the time it was diagnosed. And this should especially be considered in patients who seem to initially respond well to treatment and then stop responding all of a sudden. So we know that inflammatory bowel disease can transform over time into neoplasia, specifically into gastrointestinal lymphoma.

And so we consider inflammatory bowel disease and GI lymphoma to be somewhat of a spectrum of disease, with patients with inflammatory bowel disease having more mild disease and if patients have severe inflammatory change chronically, that can transform into actual neoplastic change. And so for this reason, repeating abdominal ultrasound in cases of previously confirmed inflammatory bowel disease that continue to have severe signs or start to stop responding to therapy can be really helpful because on repeat imaging, we may see changes like some severely enlarged intra-abdominal lymph nodes that could suggest transformation of the inflammatory bowel disease into neoplasia. A second simple recommendation I'd have is to recheck the clinical history with the owner.

So, an owner may initially say that yes, they are religiously following their recommended diet trial and they're giving all the the medications that you have advised, but when they're specifically asked a little bit more, it may become clear that they are in fact giving the dog. Some treats, or you should consider the possibility that the dog is, you know, a very enthusiastic scavenger. And if a dog has unsupervised access to the outdoors, it's possible that it could be ingesting other material unknown to the owner that could be undoing the good of the medication trial or our, sorry, the, the diet trial or our medications.

A further simple thing to check in cases that are continuing to have very severe GI signs is to recheck their cobalamine status, even if you have given them cobalamine supplementation previously. So typically we tend to follow a set protocol of cobalamine supplementation. In patients where cobalammen is found to be low, we typically follow this protocol published by Texas A&M University, where we give cobalammen subcutaneously once a week for 6 weeks, then give one injection a month later and recheck cobalammen 1 month after that last injection.

Now recently, publications have also confirmed that it's a reasonable alternative to give cobalamine orally in these patients, although typically it's necessary to complete a longer course of supplementation of cobalamine if we give it orally. So typically we'll give a 12 week course if we're going to use oral cobalamine. Now, this duration of treatment, be it injectable or oral, is appropriate for the vast majority of dogs, and when we recheck serum cobalamine, it's very common that we see that it has normalised once we've finished that standard cobalamine.

Regime. However, some dogs with particularly severe disease could require longer than usual cobalamine supplementation. And so I always advise rechecking cobalamine in dogs with ongoing clinical signs, even if you have recently completed a course of supplementation.

In particular, if you've been giving a course of oral cobalamine previously, but when you remeasure carbalamine, it's still low, then I would definitely recommend switching to injectable cobalamine supplementation rather than giving further oral supplementation. And this is because we know that although we know oral cobalamine supplementation is effective in dogs and seems to be effective, there aren't any large peer reviewed studies that directly compare the effectiveness of oral supplementation to injectable supplementation. And therefore at this time, injectable supplementation of cobalammen should still be considered the gold standard form of supplementation.

And so if we have patients who have persistent hypocobauminemia, I definitely would recommend giving those subcutaneous injections at the time being until we have more evidence that the oral supplementation is just as good. It may be that it is, but at the moment we can't say that for sure based on the studies that are published. Another simple thing we can do that can often be successful is to simply change the type of diet we're offering the patient.

So usually either a novel protein or hydrolysed diet will be appropriate and will be successful if the patient has food responsive disease. But we can see individual variation in the response to either type of these diets. So what I tend to do is if you've already tried a novel protein diet and the patient continues to have signs.

I would consider switching to a hydrolysed protein diet and vice versa, as some dogs seem to respond better to the different class of food. Another consideration would be trying an ultra hydrolysed diet like Royal Cannon and allergenic, and so these ultra hydrolysed diets are even more hydrolyzed than the typical hydrolyzed diets like Hill's ZD or Purina HA. The typical hydrolyzed diets have very small protein particles between 5 and 15 kilodaltons in size, but the ultra hydrolysed royal cannon and allergenic has protein particles that are less than 1 kilodalton in size.

And this property makes the royal cannon and allergenic even more hypoallergenic than the more standard hydrolysed diets. And so it is worth trying these in patients that don't respond to the more routine diets, but I typically don't use an allergenic as initial diet trial because one downside is that the more Hydrolysed a diet is, in general, the less palatable it is, and I do find it's a lot more challenging to get patients to successfully transition onto an allergenic in the long term than it is to get them onto something like Hills ZD or Purina HA. But definitely I will consider it in cases that aren't responding to treatment as I would like.

Another simple thing I consider doing in these cases is repeating courses of anti-endoparasite therapy in dogs who are continuing to experience diarrhoea. So even if faecal parasitology results are negative and you recheck them and they're still negative, I would still treat any dog with a chronic enteropathy who is having ongoing signs with an empirical course of anti-parasite therapy. Because we know that many gastrointestinal parasites are only intermittently shed, and so we can get lots of false negatives on faecal parasitology.

So typically what I'll do is use a 5 day course of fenbendazole at a dose of 50 milligrammes per kilogramme once a day. But in cases of really severe diarrhoea or vomiting where the patients just don't seem to tolerate any oral medications, sometimes I'll consider giving a topical alternative like Cellemectin. And you know this is something you can do very simply.

It would be a shame to miss something as simple as gastrointestinal parasitism before you go into more kind of extreme or involved forms of therapy. So it's something simple to do and something I would always do even if the faecal parasitology is negative in these cases. One thing many owners will ask you about and something most of you have probably used in practise is probiotics, and short term courses of probiotics you may have used like Procoin or Canoure, to name a couple of brands, are commonly dispensed for management of acute diarrhoea and sometimes longer courses of these probiotics are given to dogs with chronic diarrhoea.

Now studies in dogs and in humans have shown major changes in the composition of the gut microbiome, in patients with chronic gastrointestinal diseases. So there definitely seems to be a rationale for using probiotics in patients with chronic diarrhoea to try and rebalance the flora of the gut. Now, although this seems to make sense and sounds appropriate, a recently published systematic review looking at all of the published studies on the efficacy of probiotics in dogs, failed to show a significant benefit in any studies in terms of reduction of clinical signs or improvement in quality of life.

And so this has really called into question in the last couple of years how useful probiotics really are in these cases. Now, despite this, it is worth noting that the studies that have been performed that were included in this review, all involve quite low numbers of animals and all had quite short duration of follow up. And therefore it might be in the future when we have some more higher powered studies performed, we are actually able to prove that probiotics have a reasonable efficacy, but we just can't say that really at the moment.

Despite there being a lack of published strong scientific evidence for probiotic use, anecdotally, some patients do seem to have a positive response to probiotics, and so, although I will rarely give them as a first line treatment in chronic enteropathy. These like inflammatory bowel disease, I do consider them in cases where standard therapies aren't are are failing because these won't do any harm. As to how much they will work is questionable, but definitely anecdotally, some patients do seem to have a positive response.

Now there are lots of different probiotics on the market, and again we don't have any high quality studies comparing the effectiveness of one type compared to another. But if we extrapolate from human medicine, multi-strain probiotics, that is probiotics that contain multiple different species and strains of bacteria, seem to be the most effective. And in veterinary medicine, the one type of antibiotic we seem to have the most evidence for it having some type of effect is called VSL number 3.

Studies on this probiotic in dogs have documented it does improve inflammation on histopathology in dogs with chronic enteropathies. Although studies looking specifically at whether or not it actually improves their clinical signs are lacking. Now, this is a probiotic that can be ordered online, and it comes in sachets of powder.

And typically what I'll advise owners to do is give half a sachet of the powder once a day with food. And anecdotally, you know, lots of owners seem to report that within 3 to 4 weeks of starting the probiotic, they do report a significant improvement in the patient's sign. It is quite an expensive probiotic, so it costs, maybe around 30 pounds sterling for a one month supply for an average sized dog.

But it is worth considering, you know, if you're at your wits' end trying to manage these patients, and if the owners are up for it, if they're very committed and wanting to do everything, I, I definitely will mention this probiotic VSL number 3 to them. And I think it is the best one out there, at least at the moment until we have more studies to help guide us as to whether any others are better. Another thing to consider is that although typically we will start immunosuppressive therapy with prednisolone as a single agent, some severely affected dogs may require two types of immunosuppressive agents used concurrently to control their clinical signs.

So, most commonly we will use cyclosporin, chlorambucil, or azathioprine as the second agent. Some vets will also consider an immunosuppressive called mycophenolate, but I personally prefer to steer clear of this agent because it has the most adverse gastrointestinal side effects, compared to the rest of the drugs, and that's obviously something we want to try and avoid in patients with severe diarrhoea or vomiting. So personally, I tend to choose cyclosporin if the owners can afford it, because it kicks in more quickly than the other types of immunosuppressives.

And usually the dogs we're going to need to use a second immunosuppressive agent in are quite severely affected and so we usually want something that's going to kick in and start working relatively quickly. It's important to also, like with prednisolone, use an immunosuppressive dose of the second agent immunosuppressive drug to make sure we're getting the optimal response. So for cyclosporin, I'll opt for a dose of 5 milligrammes per kilogramme twice a day with the ultimate goal to again slowly taper off that with time, like we do with the prednisolone therapy.

I also consider quite commonly adding additional fibre into the diet of dogs with severe diarrhoea, and I think this is something we really underutilize in veterinary medicine. I tend to find additional fibre most helpful in dogs with signs of severe colitis. So those dogs that are displaying severe tensmus and discomfort while defecating seem to commonly respond very well to additional fibre supplementation.

The one I personally like to give is psyllium husk. I find it a really good fibre supplement. It's easily purchased from human health food shops, and I find it so good because it has an ideal ratio of soluble to insoluble fibre.

So the soluble fibre, pulls in and swells up with water in the stomach, partially dissolving within the stomach to form a thick gel-like substance. That helps slow down digestion as it passes through the gastrointestinal system. And the insoluble fibre passes through the entire gastrointestinal system unchanged, but it can help to bulk up faeces.

We don't want too much of this insoluble fibre because it can increase the speed of transit of intestinal contents and make diarrhoea worse if given in large amounts. But giving both types in a good ratio. With soium husk can help regulate bowel movements and can greatly improve the quality of life, particularly in patients with severe colitis.

So this is definitely something you can utilise. It's fine to give it along with hydrolyzed or novel protein diets. It shouldn't affect the effectiveness of the diet trial, because this is just additional fibre, it's not an additional protein source.

So, something worth considering and something that's not overly expensive either. And finally, I'd like to touch on a couple of things that I would generally consider as more or less last ditch efforts for cases that aren't responding to anything else. For dogs with refractory colitis and straining, I'll sometimes consider using sulfasalazine.

So this is an anti-inflammatory drug that acts locally in the colon. Around 90% of the ingested drug reaches the colon unchanged, and there it's broken down by colonic bacteria into active metabolites that exert anti-inflammatory effects. We don't know exactly how this drug exerts its anti-inflammatory effects, but it does seem to really help in some refractory colitis cases where prednisolone therapy doesn't seem to be helping.

One important side effect of this drug is dry eye, so if you do have a patient on it long term, very important to perform chert testing. Another drug I'll sometimes use is Semethicone, which is anti-forming agent that decreases the surface tension of gas bubbles within the stomach and intestines. And this helps to combine them into larger bubbles that can pass through the digestive tract more easily.

So this property can be really helpful in dogs who have signs like severe flatulence or severe bloating. And this isn't a drug commonly stocked in veterinary hospitals, it's not one licenced for dogs, but it can be used off-licensed. It is available in most human pharmacies.

Over the counter medication. And, if I'm going to use it, I typically will dose it kind of to the equivalent human dose. So if we say an average human weight is around 60 to 70 kilogrammes, then if I have a 30 or 40 kilogramme dog, I'll probably give the dog about half the human dose listed on the packet.

And it does seem to help, particularly in dogs with lots of gas and lots of bloating. And finally, therapy that has received a lot of attention in human medicine in the last few years is faecal transplantation. And this has been performed in some dogs, although there aren't very many studies looking at it yet.

In simple terms this is transplantation of faecal matter from one dog, to another, and there's not really a consensus on the optimal approach. And so several different methods of transplantation are described. Whatever the approach, we usually will choose a donor dog.

That is healthy, has no gastrointestinal signs, and is up to date on routine endoparasite prevention. We also want to make sure that the patient has faecal parasitology and culture performed before we use them as a donor, so that we're not introducing any harmful microorganisms or parasites that could make the recipients signs even worse. And most people will give a slurry of the donor faeces mixed with water via endoscopy into the duodenum and will also instil it directly into the rectum via an enema, whereas other clinicians describe just giving it via an enema alone, which is probably a less invasive way because that can be done consciously in most patients.

Now, faecal transplantation is very much in its infancy in veterinary medicine, and so overall data is limited in terms of how effective it is. But there are some amazing results reported in human medicine using faecal transplantation in cases like Crohn's disease. So I do suspect that in the next decade it will become a more routine treatment for chronic enteropathies in dogs.

It's not a very pleasant procedure, and so it's not something we would want to perform really as a first line treatment unless we had lots of evidence it was going to work. But again, if you feel like you've tried absolutely everything, you have a very committed owner, you know, it's something that is there. There are some studies evaluating it in dogs.

Anecdotally there is some good, there, there are some good responses reported. So, you know, why not try it, if, if you feel you've exhausted every other option. So, that concludes this webinar on the management of inflammatory bowel disease and managing difficult cases.

I hope you found it informative and helpful and I'd be happy to answer any questions. Miles, that was absolutely fantastic because we often get to these places where we just go, oh, I've done everything, what now. And this is fantastic, where you go back and you start logically looking through it.

So thank you for sharing your thoughts on that and giving us a much more or giving me anyway, a much more systematic approach to these difficult cases. You're welcome. So Liz has asked a question and she says, if you have a dog with chronic GI signs, which is metronidazole responsive, but recurs even if if the metronidazole is missed for a few hours, how would you go about weaning it off or or approaching it?

Yeah. So, I guess my feeling would be that so if the dog is responding to metronidazole therapy but doesn't seem to be able to manage off metronizole therapy at all, then, you know, that is indicating a more aggressive form of the disease. And so I feel like that patient is one who would probably benefit from gastrointestinal biopsies and immunosuppressive therapy, because.

Antibiotic responsive enteropathies, if the disease is truly antibiotic responsive, we should see that they're able to control their clinical signs of antibiotics for at least a few weeks in between courses. And so typically in those patients, I will consider immunosuppressive therapy, because they probably have a more severe form of the disease than just these truly antibiotic responsive cases. Right, so something else underlying with it.

Exactly, exactly. Yeah. Lisa's asked a question, and said, would you ever consider allergy blood tests for IBD cases?

Yeah. The honest answer is no. And so there, yeah, these certainly are on the market and I, I think lots of owners are very keen on them because I think owners love to see all the different food types and, you know, what the dog has seems to have antibodies to.

But the thing is that they don't really alter how we would treat the patient, so just say we do a allergen blood test and we find that the dog has antibodies to chicken. It doesn't mean that the dog is actually intolerant to chicken and that that is the food type that is actually, causing the dog to have these signs. So if a dog has eaten chicken at any time in its life, it can have antibodies to that in the blood, but it doesn't mean that it has an intolerance at the level of the gut.

And so none of the allergen tests are really reliable. And, and they don't really add anything in clinically, that's relevant, because they don't really correlate with which food types are causing this inflammatory response in the gut. So the only way to really know what food type is causing the abnormal reaction in the gut is to cut all food types out and just put them on a hydrolyzed or novel protein diet.

And then one by one, if the owner wants to and is brave enough, once the clinical signs have sett settled down. Then they can try to reintroduce the food types one by one, and see which food type the dog actually has a bad response to. And so that's the only way we can know for sure what food type causes this response.

The allergen blood tests unfortunately don't help in that regard. In my experience, by the time you get that tummy to settle down, the clients are just so grateful. They don't want to risk it anything that's I think it's a bit more academic than something that is beneficial practically really.

Yeah. Yeah. I'm not really sure Gideon has made a statement here or what maybe you can understand it.

He's just said, smethicone, avoid artificial sweetness. Yeah, so with immethicone, I guess it is a over the counter human medication. And so it's always good to double check, you know, whenever you're using these that they don't contain Xylitol or anything like that, which would be obviously a disaster.

The ones that are commonly available over the counter. In the UK, you know, tend not to have Xylitol in them. But, you know, I would always, yeah, I, that's a really good point.

I will always get owners to double check that, because the last thing we want to happen is to inadvertently give them Xylitol toxicity, even if we successfully control their gassy stomach very well. That wouldn't be good. So, so avoiding the, the combination that Gideon was referring to.

Exactly, yeah. Excellent point. Thanks, Gideon.

Well, Miles, we've come to the end of the questions and we've come to the end of our hour. So thank you once again for your time and for presenting us with a, a very logical way to deal with these sometimes very frustrating conditions. You're very welcome.

Thanks very much. And to everybody for attending tonight, thank you very much from myself, Bruce Stevenson, it's good night.