Hello everybody and welcome to this lecture on immune mediated polyarthritis brought to you by myself, James. So this lecture is going to be hopefully everything that you need to know to investigate, diagnose and treat these patients successfully in a primary care setting. And I will also reference these patients at referral level as well, but certainly this is something that can be picked up and managed in primary care practise relatively easily with, you know, the sort of standard equipment and levels of training, you know, that are out there in primary care practise.

OK, so why are we talking about IMPA? Well, firstly, it's a common but probably quite underrecognized condition, so it's quite important to have an awareness of this disease because it could be on the differential list of quite a few different presenting problems. And some of these patients don't always coming in screaming, I've got to mean mediated polyarthritis, and the only way we can sort of definitively diagnose it is on joint sampling these patients.

So we just need to have that awareness about not overlooking the utility of joint sampling in some individuals. And ultimately IMPA is a synovitis, so an inflammation of the synovial capsule and of two or more joints. Which responds to immunosuppressive therapy.

It typically affects young to middle aged dogs of any sex or breed. Although older dogs and younger dogs can be affected as well, and it can cause signs of systemic illness as well as some of these typical sort of classical signs of joint pain and inflammation. And, and an important thing to remember in these patients as well is there's actually quite a variable response to therapy.

So sometimes the actual diagnosis is not the most challenging part of managing these cases, but actually the treatment and ongoing monitoring as we'll get to. So onto the pathophysiology, we can think about IMPA, as the non-erosive and erosive form. So firstly, the non-erosive form.

This is by far the most common form and counts around 95% of IMPA cases, and, ultimately, it is a type 3, hypersensitivity reaction. Which leads to deposition of immune complexes in the synovial basement membrane, secondary to an immune stimulus, whether that's a distant immune stimulus. Or whether it's primary autoimmune, and this leads to inflammation of the synovium itself, which is a primarily, neutrophilic inflammation.

So the erosive form is far less common, very, very rare in fact, and when we do see the erosive form, it's most commonly due to the activation of plasma cells or T cells which produce something called rheumatoid factor, which is a pathogenic immunoglobulin, which causes in fact a type 4 hypersensitivity reaction. The rheumatoid factor is deposited in the synovium and phagocytos. Inflammation then ensues, as well as importantly, in the erosive form, the activation of the osteoclasts.

And it's ultimately the activation of these osteoclasts that leads to bone resorption around the joints, and then fibroblast proliferation can lead to scarring and deformation of the joints. And as we'll get to a little bit later on, the erosive form of the disease causes much more severe clinical signs and long term consequences, including, as I say, significant deformation of the joints, but we'll get to some. Really graphic examples, a little bit later on.

So the non-erosive form of IMBA can be further subclassified, depending on sort of which sort of system you want to use, which way you want to look at it. And so for many years we've been using the Type 123, and 4 system, which is adapted from humans, in which type 1 disease is idiopathic, a primary autoimmune disease. Type 2 is reactive, generally to distant, inflammation, or infection.

Some examples of that include things like, bacterial endocarditis, a bacterial infection of the mitral or aortic valves, and triggering secondary inflammation in the joints, but we could see it with any disease that causes inflammation, infection elsewhere in the body. Type 3 reaction, that's secondary to gastrointestinal and hepatic disease. So you may have a patient who has primary IBD, and that's triggering, a secondary immune-mediated polyarthritis.

And then type 4, is distant neoplasia as well, triggering, a new mediated polyarthritis. And with these patients, who have the secondary disease, these are the ones that, you know, we hope to pick up with our thorough. Because identifying an underlying trigger for the disease means that we often focus the attention of our treatment on that underlying disease and less so on the actual IMPA itself because if you can treat that underlying disease, often the IMPA will resolve.

So this is the way that we've been classifying patients for quite a long period of time, but more recently we've started to move away from this and think perhaps it's just easier to consider patients either primary or secondary. So the primary being the idiopathic autoimmune form of the disease, and secondary being just any distant immune stimulus. So certainly the primary form of the disease is the most common.

And is ultimately a diagnosis of exclusion. So we'll get to a little bit later on, it just highlights the importance of really digging deep in these patients to rule out all the secondary causes before we launch sort of headstrong straight into immunosuppressive therapy. So thinking about the secondary causes of IMPA, there's really quite a few things to consider.

And we've already mentioned in distant infection, inflammation, neoplasia, GI disease, hepatic disease, but medications as well can cause it. And the most common of which is the sulfonamide group of antibiotics. We already know that they can cause quite a few different sort of complications in our patients, so it's just another one to add to that list of considerations when prescribing the sulfonamide.

And but also erythromycin, cephalosporin antibiotics, penicillin-based antibiotics, and phenobarb as well have all been shown to induce secondary IMPA in some patients. And in these individuals, if they develop IMPA, the removal of that drug should really limit the ongoing inflammation, and these patients should improve significantly, quite often without the need of immunosuppressive therapy. Vaccination is something as well that's been identified, and often vaccination can induce a sort of quite mild transient form of IMPA that develops within a few days of vaccination and does self resolve again within a few days or even a week and often without the need.

For, you know, immunosuppressive therapy, and these patients are, in my experience, most commonly kittens, and they just develop a little bit of malaise, a bit of stiffness, and a few days after vaccination are often brought back by their owners for a recheck. They're simply just by observing them and giving them enough time. And this transient sort of mild form of IMPA is often self-limiting.

IMPA may also be associated with polysystemic immune mediated disease such as systemic lupus erythematosis, in which it's simply one component of several. Bodywide autoimmune diseases, you know, including autoimmune skin disease, immune mediated thrombocytopenia, immune mediated hemolytic anaemia. And we also see a few different breed associated forms of IMPA.

So the Japanese Akita has their own form. Sharpes, they also have their own form of sort of IMPA associated with sharp a fever, which is a sort of a systemic inflammatory disease. That leads to inflammation within the joints, which is often actually responsive to nonsteroidal anti-inflammatories rather than the need for immunosuppressives.

But more importantly in this breed we get amyloid deposition within the kidneys which leads to sort of progressive proteinuria and kidney disease in these individuals as well, so quite a progressive form of disease in the shar pei. And beagles as well overrepresented and greyhounds also. Have the erosive form of IMPA.

So we'll get to sort of the slight difference of the work of these patients a bit later on. But if you have a greyhound, for instance, that presents with signs of IMHA, you know, you're also be thinking this patient may be a risk of the erosive form, you know, and warrant a little bit of further investigation in respect of that. So what are the clinical signs to look out for?

So sometimes these can be quite subtle, and this is why a large number of these patients often end up at referral level because they just don't walk into the practise always screaming, I've got IMPA, you know, it's not one of those easy peasy pattern recognition type diagnoses. Often the clients will report that the pet is just reluctant to walk. They seem a little bit of a stilted gait, a little bit stiff, perhaps hesitant, to jump up and up and down off of the bed or the sofa, difficulty getting up and down the stairs.

And just generally looking uncomfortable and perhaps just not wanting to walk. And we can see a shifting lameness, but these lamenesses that we see, I think they're honestly sort of somewhat subtle in that there is not one individual leg that this dog is hoppingly lame on, but because they're just generally sore on multiple different joints and they're not moving around much, it is sometimes hard to really Appreciate a significant lameness in one individual limb, but even when you do, that lameness can seem to shift between the different limbs, you know, whether you see the dog on one day and you think oh perhaps this dog's got a right hind limb la maybe it's a cruise ship rupture, and then they come back for a recheck, you know, after NSAIDs a week later and it then seems to be in the left hind limb. And we may detect multiple aused joints, but we may not.

So it would be nice and easy if IMPA patients all came in with a fused joint to really help us in identifying them, but unfortunately a significant percentage, about 50% of patients do not have palpably refused joints. Now those that do, it's most commonly the distal joints that we feel are fused, so particularly important ones to get used to palpating of the carpa and the tarsi. And what you can feel there is just a bulging of the synovium as that joint is more refused.

So they can just feel, a little bit sort of puffy and bulgy, the joint spaces. And of course they can be painful and manipulation as well, but again only about 40% of patients, are painful when you manipulate their joints, overtly. So again, it just makes it a bit tricky to pick up in some individuals.

But sometimes also associated with effusion, you can get a bit of peripheral subcutaneous edoema localised around the joint itself, and some of these dogs can therefore present and just with the naked eye you can visually see that they have quite sort of puffy tarsi and carpi. I find this particularly evident in sighthounds such as whippets, which normally, you know, have very skinny legs, with very little sort of connected. Tissue and fascia underneath the skin, and you can visually appreciate that these, these dogs have got swollen, joints with, subcutaneous sort of edoema, and it's pitting edoema as well, so if you pinch that area, it forms a little bit of pitting edoema.

So weight loss is not uncommon in these individuals as well because of their degree of systemic illness. They often have a reduced appetite. You know, having a significant inflammatory disease increases your calorific requirement, and it's not uncommon for these patients to present with a degree of weight loss and that sort of highlights the fact that whilst this disease is primarily centred on the joints, it really is a systemic illness that causes, you know, inflammation throughout the body.

And then about 50% of our patients are pyrexic. And so always important to check the temperature in these individuals, and it'd be sort of unusual for a patient with joint disease to have pyrexia for any other reason other than IMPA or perhaps a septic arthritis. Now one important thing to help to help us differentiate septic joints from non-septic polyarthritis is simply the fact that a septic joint is typically an individual joint.

When you have one joint that is very inflamed and sore, but all the other joints appear normal, that is kind of more suggestive of a septic joint, whereas when you have multiple joints inflamed, that's much more, suggestive of non-septic, inflammatory disease. Also, the septic joints tend to be less commonly, the carpine tarsi, and certainly in my experience, elbows seem to be the most common joint to develop sepsis. So you know, if the breed isn't quite right, well, not the breed because it could affect any breed, but perhaps if the age of the patient presenting isn't quite right, you know, they're very, very old.

If it's only one joint that feels inflamed and sore, you know, and particularly if it's not a carpus or a tarsus, then yes, certainly don't overlook the possibility of that patient having a septic joint because that's a very different approach to the investigation and treatment, of course. So on to the investigation of these patients, it's quite a thorough set of testing that's required, ultimately to diagnose IMPA as a diagnosis of exclusion, as we've already said. To rule out any other sort of comorbidities, any of the triggers of that inflammation, so it is quite a detailed work up in many ways, but still one that can be achieved in primary care practise.

And so the first thing that we're going to do is a biochemistry and haematology. And what we typically see there is an inflammatory leukogram quite often with a left shift on the haematology. And now that's of course very non-specific.

It just tells us there's inflammation in the patient, but it doesn't tell us what type of inflammation necessarily, and where that inflammation is. But it's a good thing to look out for because it'd be very, very uncommon for a patient with immune-mediated polyarthritis to present without an inflammatory leukogram. And also on the leukogram, we may get a mild non-regenerative anaemia if that disease has been present long enough, it can induce a mild anaemia of chronic disease or chronic inflammatory disease.

We may also see some changes in the platelet count. It's not uncommon in patients who have significant inflammatory disease to have a mild thrombocytopenia. Because of consumption of those platelets during the inflammatory disease process, again, we may also have particularly low platelet counts if the patient has a concurrent immune mediated thrombocytopenia.

So as per the ACBIM consensus statement in those patients, we're typically looking for a platelet count below 20 times 109 per litre. So haematology is very important in these patients, and biochemistry, I suppose somewhat less so. Typically the biochemistry is largely unremarkable in these individuals, but what we are looking for is any evidence of comorbidities.

So do we have elevations of the liver enzymes to suggest a primary hepatopathy? Do we have, a significant hypoglobu anaemia which may suggest chronic infection, neoplasia. Yes, of course, it could be chronic inflammation as well.

And the identification of a hypoglobulin anaemia may mean that we want to dig a little bit deeper into neoplastic in infectious causes. And we may consider running a serum protein electrophoresis to try and differentiate a polyclonal from a monoclonal gammopathy, and with polyclonal gamopathies being primarily caused by infectious inflammatory disease, whereas monoclonal gammopathies typically caused by neoplastic disease. And We may see mild hypoalbinemia in these patients.

Because of inflammation, we may see slight alterations in the glucose being slightly high because of systemic inflammatory disease, but otherwise the biochemistry is often largely sort of unremarkable in a lot of the primary IMPA patients. So we want to combine biochemistry in all cases where possible with a urinalysis. So we're going to check the urine specific gravity, make sure that the urine concentrating ability is normal, and we're going to culture the urine and see if there's any evidence of a urinary tract infection there that could potentially act as a trigger for our IMPA, although it would be quite uncommon, but also whether or not there's any UTI there that we need to worry about getting worse if we're going to start this patient on immunosuppressive therapy.

And ultimately we'll also have a look for proteinuria in these patients. Now it's really quite common for IMPA patients to have a degree of proteinuria because of a secondary immune complex glomeulonephritis. Essentially, inflammatory disease elsewhere in the body causes immune complexes to be deposited within the glomerular basement membrane, and this damages it, leading to it being leakier than normal and the patient losing.

Proteins more so than they should do. So this is something that we often want to pick up at this stage and monitor. A lot of these patients, when you treat the underlying inflammation, their proteinuria will resolve, but some patients who have particularly profound proteinuria or persistent proteinuria may warrant anti-proteinuric therapy.

Longer term in the form of an ACE inhibitor or Telmisartan and perhaps, to help improve their outcomes. So your analysis, you know, generally always very important, in our investigations, but particularly so in these patients. And we're then going to consider the patient's travel history.

So really important to know which regions of the world this patient has been to and what diseases are endemic there, because there are certainly regions of the world in which there are several endemic diseases that can lead to a secondary immune mediated polyarthritis. And we need to therefore test for those. So typically patients who've travelled to areas that are at risk of sort of Eliia, anaplasma, diaphylaria, we'd recommend an IDEX 4DX snap test just to screen to see if there's any exposure to those and to see therefore if they warrant any treatment or whether they could be associated with the cause of the IMPA.

And but also Leishmania serology as well to those that have travelled to endemic regions. And even if the patient isn't presenting with sort of classical dermatological changes associated with the leishmania, and you know they don't have any aotemia, it's still definitely very sensible, you know, to screen for that disease. Now do bear in mind as well that the 4DX snap covers for Lyme's disease, so Borrelia bugorri, which is also a secondary cause of IMPA in patients from, from the UK, and that disease is endemic to the UK.

So really important test to run this in the IMPA patients because picking up the Borrilllia patients at this stage is really important so that we don't go down the route of immunosuppressive therapy. And potentially make these patients even more unwell than they already are, because actually they just need treatment of that Lyme's disease with specific antibiosis. So to complement the blood work, we also want to do imaging.

So as a minimum, we want to look at thoracic and abdominal imaging and, a minimum of two peripheral joints that are imaged. So the thoracic and abdominal imaging is important, to look for, secondary causes of the IMPA, so neoplasia, infectious foresite, and, and inflammatory foresite, . This can be done in the form of thoracic radiographs.

And abdominal ultrasound in primary care practise, and commonly at referral level is done with the use of advanced imaging, with CT scanning, just because of its higher, sensitivity really and specificity in many cases. Now, one thing to bear in mind is that whilst we're looking for secondary causes of IMPA, as this paper from, 2024 demonstrated, it's very actually uncommon that we do identify anything on the thoracic and abdominal imaging. That actually changes the diagnosis and treatment plan in these patients.

So, it's a bit of a, a tricky one in that we, we really have to do it to be sure it's not a secondary IMPA, but we're often doing these tests, really expecting them to be normal. To help us sort of rule out any of those secondary causes, so it's still not to be overlooked, but I suppose, you know, if we did have a case, you know, presenting primary care practise where finances were really, really restricted and we had the option of either just treating this patient or working it up, it certainly would be reasonable to say, well, OK, perhaps we can skip the thoracic and abdominal imaging to save enough money to sample joints and start immunosuppressive therapy. You know, and if we sort of stoppressive therapy, there's no clear evidence of any secondary causes, and the patient responds to those drugs, then, OK, we've probably got the right diagnosis.

But generally speaking, you know, the thoracic and abdominal imaging should be considered and performed. And we then image to peripheral joints really to exclude the presence of erosive disease, or any other joint pathology that can mimic IMPA. So sometimes you will get caught out by other diseases as well, like pan osteitis, for instance.

And these patients, you know, can be differentiated based primarily, you know, on their radiographs, . The erosive patients, you know, they can have really quite significant changes on their imaging, and they're typically not challenging to diagnose. And now the types of changes that we can see include joint diffusion, which we'd also expect with a non-erosive form of IMPA, but pretty significant subchondral bone erosion as well.

Luxation of the joint and ankylosis, although the latter may not be present, in the early disease and only in the latter disease. Now, on the screen, these images are taken from a paper, As referenced on the left here, just giving some examples of the different types of changes that we can see sort of radiographically from this 2016 paper. Now I'm no orthopaedic surgeon, you know, I look at radiograph A and say that looks largely normal to me.

Perhaps there's, yeah, some reused joints. I'm not sure. B clearly shows, you know, swelling of that synovium, but then as we move on to C and D, we see these really, you know, advanced.

Bone changes, including the erosion, luxation, you know, and ankylosis that really is sort of unmistakable for this disease process, although I suppose in some instances, you know, you may be forgiven. For thinking that the changes are so advanced, it could be suggestive of osteomyelitis or neoplasia, you know, perhaps in some of those individuals if there's an index of doubt about the radiographic diagnosis sampling may be performed. But as you can see on radiography, it just really highlights the horrific sort of end stage nature that some of these patients can present with with the erosive form of the disease.

And when they get to this stage, obviously the prognosis is really quite grim in that we may be able to switch off the information if we're lucky in these patients, but the damage has already been done with significant, you know, remodelling of the joints and bones. So these cases, you know, can be very, very challenging and and the best, you know, worked up at a site that has both internal medicine and surgery services for a sort of combined approach to the management of these individuals. So just on to arthrocentesis, so arthrocentesis is something that Can be challenging when you start doing it.

Particularly because we're most interested in those peripheral joints, the carpine, the tar side, however, With a little bit of practise, it is certainly manageable to be able to sample these joints, you know, in primary care practise, with the availability that we have to sort of, learning references, and lots of good references such as BSAVA, you know, manuals and Various of the textbooks that give really nice pictures on exactly where and how to sample all the different joints. Now that's beyond the scope of today's lecture to go through all of those, but essentially it is something that can be achieved, particularly in the IMPA patients, because a good 50% or more of them really do have quite swollen, well aussed joints, and that makes them a lot easier to sample. Much easier than patients who have degenerative joint disease, where there is much less inflammation and synovial swelling, but also the bony remodelling that we see in those patients can sometimes make it a bit more challenging to sample the joints.

So in these individuals, we do have to sample the joint to document a polyarthropathy, and we do need a minimum of 3 peripheral joints. So typically I would start out looking at both carpi, both tarsi. And if we can sample all of those, then that's great, and if we're struggling with those joints, then we can move a bit higher up the limbs to sample the elbows and the stifles.

This is generally performed under general anaesthesia, and I would do this at the same time as I perform my thoracic, abdominal, and, distal joint imaging. They can, however, be performed under heavy sedation. However, again, in my experience, normally if we're doing thoracic imaging, we're going to want nice inflated, 3 views of the thorax and to be able to get those who want to have the patient intubated and have control of the airway.

So normally it is under general anaesthesia, . We do, analges our patients. However, it's quite normal for these patients to wake up and be very comfortable after joint sampling.

It's not a painful procedure. So we don't have to get too worried about the use of sort of local techniques and things like that. So the patient is anaesthetized, and we have to clip and aseptically, prepare the joints, that's really important, because there's always a very small risk of introducing infection into one of those joints.

And also if you're particularly new to doing joint sampling, you know, it might take you several goes to sample each joint, and the more attempts you have at that joint, the more likely you are to introduce, bacteria. So really important to do a nice wide clip and aseptic preparation. And then get yourself an appropriate size needle so you can get away with smaller needles for the carpine tar side, but certainly larger needles can be beneficial in stifles and elbows and make sure they're nice and long, particularly those elbow joints and stifles of large breed dogs.

You're looking at needles over 1 inch in length. For those patients to be able to sample effectively. And you then use 2 mL syringes, and you need to get yourself some pots as well for your joint fluid to go into.

So a plane tube for the fluid analysis and proteins, EDTA tube for cytology, and potentially PCRs, but also some glass slides as well for fresh smears. Now some people as well will put joint fluid samples into blood culture bottles because we're going to want to culture these to make sure there is no evidence of bacterial infection, and some people will advocate the use of blood culture bottles to help improve the likelihood of getting a growth if there is a bacteria there. So once we have a patient anaesthetized and aseptically prepped, you're going to be wearing sterile gloves and you're going to get each joint to be mobilised and sort of, well, not mobilised, but angled in a position that's comfortable for you to sample and flexed or extended to the right degree.

So that you can then access that synovial fluid as easily as possible. The needle goes into the joint, slight bit of negative pressure to aspirate the joint fluid, and as you aspirate the joint fluid, you just make sure that you're not aspirating too hard or moving the needle too much, or aspirating as you pull out because you want as little blood contamination of that sample as possible. And in some patients, particularly from the larger joints like the stifle, you may get 0.5 mL, 1 mL of joint fluid, and that's more than enough for you to make some fresh smears with to place in a 0.5 mL UTA and have some in plane tube as well for culture and protein.

Levels. However, for some of the peripheral joints, even in, in some larger breed patients who do have inflammation, it's not the easiest thing in the world to get a large volume of joint fluid. And sometimes you may even have enough just to fill the hub of the needle, and if that's the case, the most important thing that we're going to want to do is perform those, fresh smears for cytological evaluation.

So if you only have a tiny amount of fluid, straight onto a fresh smear, and get it air dried, that's probably the best thing that we can do, with that. Also, when you take out the fluid from the joint, you want to assess its gross appearance. So you can look at the colour of it.

It should be colourless, whereas when there is significant inflammation, it can become really quite discoloured, almost a sort of brownie type colour, and we can look at the the sort of turbidity. So normal joint fluid, you should be able to see through it, whereas when you have significant inflammation, it can become somewhat sort of opaque and not possible to see through. And you can also put a little blob of joint fluid on your thumb and index finger, and if you push the thumb and index finger together and then slowly pull them apart, you can assess the viscosity of that fluid.

So normal joint fluid as you pull apart your index finger and thumb. You should have like a sort of elongated string of joint fluid stretching between the two as it maintains its relatively high viscosity, whereas with inflammation of the joints, the viscosity lowers and that fluid becomes a lot more watery, and you don't appreciate that same effect. So that's something that you can just.

Get used to doing to assess the gross appearance, but ultimately what we're going to do with these samples is submit them externally to a pathologist for interpretation. However, I do highly, highly recommend you guys get used to looking at one of those slides under the microscope in-house because the documentation of a neutrophilic pleocytosis is not the hardest thing in the world. So if you're seeing heaps and heaps of neutrophils in that sample and you're not seeing any bacteria intra or extracellular, you know, you can already be quite confident that patient likely has, an inflammatory polyarthropathy.

And depending on the individual patient, you may have a high enough index of suspicion at that point to start them on immunosuppressive therapy and whilst you wait the external test results, particularly in a patient that's really suffering particularly badly with their form of disease. Oh, so yeah, as we see here, here's an image of a patient who's got an inflammatory effusion, and lots of neutrophils there on that slide. And when we submit it to the pathologist, and what we typically see is that cell counts, nucleated cell counts, over 3000 cells per microliter and protein levels of over 2.5 grammes per deciliter.

With these non-degenerate neutrophils being the primary cell type. Do bear in mind that, yeah, the above may be influenced by prior glucocortico use. So as with any, immune mediated disease, they're a lot easier to diagnose prior to the use of glucocorticoids.

So I really would highlight the importance of doing that in these patients to the owners and not saying, well, you know, if at all possible, let's not just have a stab with prednisolone and see how they get on, because As we'll get to in the treatment part, there's a significant proportion of patients who don't respond actually that well to prednisolone therapy. And in those individuals, you know, we then need to work them up because we don't really know whether or not they're not responding well because they're just prednisolone non-responsive IMPA or whether they have something else. And once you start with the Preds, it makes them a little bit harder, to investigate.

So we also want to culture these joints as well, as I say, to make sure, that they're not septic. However, we need to bear in mind that even in septic arthritis joints, only about 40 to 50% of patients actually culture positive. So, Pardon me, just, just do bear that in mind, OK?

With respect to further testing, an anti-nuclear antibody can be considered if suspecting SLE in these patients. CSF analysis may be performed if we suspect you concurrent SRMA, as some patients can present with both SRMA and IMPA. UPC proteinuria is pretty sensible as well.

There has been publications such as the one on the right that has documented significantly increased proteinuria in dogs with IMPA, which may require anti-proteinuric therapy, but normally with these patients by treating the underlying IMPA, we do expect resolution of the proteinuria over time. And we may test for rheumatoid factor as well for erosive polyarthritis. However, it's not a particularly reliable test that has a reasonably low sensitivity and specificity for the disease, and in fact we're probably just better diagnosing that based on the results of imaging and joint sampling.

So on to the treatment of these guys, essentially, we treat the primary IMPA cases with immunosuppressive therapy. The case, the cases who have secondary IMPA, we typically treat the underlying cause. And expect the, secondary joint inflammation, to resolve following that.

Sometimes patients who have a secondary IMPA may need a shorter course of prednisolone and at a lower dose just to help get them through a problem period. And the need for that, you know, can be judged on a case by case basis based on the severity of their signs, how long we think it will take to respond to treatment of the underlying condition, . And how well they'll tolerate corticoid therapy, particularly with respect to could it actually cause significant side effects or complications in that case.

We often combine, immunosuppressives with analgesics as well. And there is a variety of different analgesics that can be considered. So opioids can be particularly useful in the poor acute patients, particularly whilst they're hospitalised, whether they're full or partial opioids, gabapentin could certainly be useful as well.

And then of course all these drugs are safe to mix with. Immunosuppressive therapy, paracetamol as well, often a good one, for, for outpatient therapy, and, amantadine as well. But ultimately immunosuppression really is the cornerstone of treatment.

And prednisolone is of course the go to drug in these individuals. We typically use prednisolone at immunosuppressive doses, so this is 2 migs per kg, orally once daily, or if you've got a dog over 20 kilogrammes, that dose of that dose of prednisolone at 2 migs per kg will be a relative overdose. Because of the actual size of that patient, when you get, over 20 kg, essentially we like to instead calculate the dose based on the patient's body surface area, as it just gives a slightly lower and more sort of accurate dose.

So 40 metre squared if they're over 20 kilogrammes, and this is the same as the recommendations for immune-mediated thrombocytopenia and immune mediated hemolytic anaemia as well. So we are looking at a very, you know, significant dose of prednisolone, and we therefore have to really educate our owners about what that's going to do to their dogs in the short term. They're going to have significant polyurea polydipsia.

They're going to be panting. They may, you know, have marked polyphagia, and they sometimes have slightly altered behaviour. And then in the longer term, of course, we need to educate about the increased.

Likelihood that they become obese, and the potential risk of diabetes mellitus, and all the dermatological changes that go along with prednisolone therapy as well, because these patients can be on this drug for a really quite a prolonged period of time, and it does cause really quite significant side effects, particularly in those larger breeds. And when we start prednisolone therapy in an IMPA case, we normally expect a pretty significant improvement within the 1st 24 to 48 hours, and that's great for the patient because they're often started on prednisolone and hospitalised during that initial day or two, and often once the prednisolone has had its chance to work over that 48 hours, the pets markedly improved and often at the point of discharge. So that's good for getting the patients out of hospitals, but also it helps reaffirm the diagnosis as well, based on that really positive response to therapy.

Typically the plan is to get patients home on this dose of 2 gig once a day, and approximately we want to taper the dose by 20 to 25% every 3 to 4 weeks. As the patient is an outpatient, sort of based on their clinical response really. Now the way that we'd monitor clinical response, is based on their physical examination, the history for the owners.

And we can can consider using C-reactive protein or other acute phase inflammatory markers like serum amyloid A perhaps even, to monitor response. So what I'd quite like to do in some of these patients is, at the point of sort of discharge or during the initial workup, just get a baseline C reactive protein on that individual. And then each time I see them back, I tend to do, do the physical examination, take the history and run a C reactive protein, and just check that in the initial stages of therapy that it is coming down, and that ideally we want this to be normal before we consider dose reductions.

The worry being that if the C reactive protein is, is high, it indicates ongoing inflammation. And that a dose reduction at that point might lead to relapse. Now do bear in mind as well that C-reactive protein, as well as some of the other acute phase inflammatory markers, are not specific to IMPA.

So, you know, if the patient has more than one problem going on, let's say they develop a bacterial bronchopneumonia for any reason, that itself could elevate the C reactive protein as well. So it's not specific. And with regards to how long we use prednisolone, it really does vary.

Some individuals will be on prednisolone for several months, with us slowly down titrating the dose, and once we get them on half a meg per kg every other day and their symptoms are controlled and they've been on that for 3 to 4 weeks, that's normally the point at which we would we would discontinue prednisolone. . Now some patients, unfortunately will require long term, immunosuppressives.

And that's been, reported to be as high as 20% of patients, as identified recently in a, in a retrospective paper, . It's the first image here we've got on the right of the screen, and essentially these patients end up on long term immunosuppressives because each time we dose reduce or we try and discontinue the drugs, their clinical signs relapse and therefore some individuals do end up on long term immunosuppressive therapy. It's interesting as well that in this paper they documented that 48% of all patients suffered a relapse at some point, whilst on treatment.

So it's a really quite a high percentage of patients, and it highlights how closely we have to monitor these patients as outpatients to make sure that they're still receiving the appropriate dose of prednisolone or other immunosuppressives and that we don't drop the dose too quickly because of the significant risk of relapse. We can also consider the use of, CBC, and urinalysis to monitor patients on immunosuppressives. Prednisolone, often causes, leukocytosis, but some of the other, second line agents that we'll talk about in a minute, can actually lead to some.

Op en ia is and of course some of the other agents as well as prednisolone, such as cyclosporin, can increase the risk of urinary tract infections. So urinary urinalysis at intervals is pretty reasonable on any patient receiving immunosuppressives. So with regards to second agents, so there's no evidence to say that a patient will do better from the outset on two immunosuppressives rather than 1.

However, this is in the non-erosive cases. However, we do recommend dual therapy in the erosive IMPA patients from the outset. Because of how much more severe and progressive their disease is and also the significant, prednisolone, side effects that that that these patients can suffer, that can lead to weakness, which can really compound their already pretty severe orthopaedic problems.

But otherwise, there's a significant number of patients with IMPA that do end up on two drugs, either because they can't tolerate the prednisolone dose, that's needed to control their disease, or they're a dog that is at significant risk of you know, developing prednisolone side effects. So let's say they're an overweight. Large breed dog, and we want to try and dose reduce their prednisolone as quickly as possible, and we can do that more rapidly if we have a second agent, on board from the outset.

But essentially about 50% of all our non-erosive IMPA patients end up on two agents to be able to control their disease. So it's not uncommon for some of these guys, you know, to have to be have one of these other medications added in. Now there's no evidence to say that any one.

Second line agent, is more effective than the others. But the four choices we typically have are leflunomide, cyclosporin, mycophenolate motil and azathioprine. Now, these all have largely different mechanisms of action, but all can be safely combined, with prednisolone.

And, and there's no evidence to say that any, any one of these is better than any one of the others. And so a lot of it comes down to assessing the individual patient and thinking about these as on a case by case basis of saying, well, OK, firstly, what's the financial situation? Can we afford more expensive drugs like cyclosporin or are we going to be limited by finances and might have to consider cheaper alternatives like azathioprine?

And what are we worried about with respect to side effect profiles of these drugs? So does the patient, for instance, have a concurrent chronic hepatitis in which azathioprine, which can be hepatotoxic, would probably be contraindicated and maybe something like cyclosporin might be more appropriate. And we also have to think about the duration of activity for these drugs to kick in and have their effects, how we're going to sort of monitor these patients, you know, etc.

Etc. So I think each individual should be assessed and the conversation I had with the owners about the options for dual therapy and which drug would seem most appropriate for that individual. .

Leflunomide has also been used as an alternative to prednisolone, in, in some studies and does seem to be, sort of non-inferior really to prednisolone in, in the studies in treating IMPA. Although generally there's a lot less sort of experience in the broader referral population using this drug than than prednisolone, . So just moving on to outcome, essentially, we need to monitor these patients closely, as I've said, during the down titration of their immunosuppression to make sure that we're monitoring for any sort of risk factors, relapse, make sure we're keeping an eye on these patients with respect to side effects of the chronic therapy of those drugs, etc.

Etc. And, but the outcome-wise, patients who've got the erosive polyarthritis, unfortunately often do have a poor prognosis with failure to control the clinical signs, need for long-term therapy, and medical therapy, and often that's combined with physiotherapy and surgery, which is often based around arthrodesis, fusion of the joints. So these patients, you know, whilst they're quite uncommon, they do have a particularly poor outcome, when we do, see them.

Otherwise, in non-erosive patients, the prognosis is good to guard it. Obviously there is a reasonable number of patients who are on immunosuppressive therapy for a period of time. They're tapered off those drugs and then are for all intents and purposes cured long term.

But there are, however, patients who do suffer relapses. After discontinuing therapy, or as I've already mentioned, it can occur whilst they're already on therapy. And, you know, and of course when you do suffer a relapse, largely speaking, the approach is if it's a minor relapse of clinical signs, go back onto the last dose of medication that you're on before the dose is reduced if you're already on therapy.

However, if it's a major relapse of signs or a relapse of signs after discontinuing your drugs, we recommend going right back to the beginning of the treatment plan. You know, going back up to 2 mg per gig once a day of prednisolone and the starting dose of any second agents that we used. So yes, some patients can be cured, some can be well managed, however, some do need long term therapy, but again in that previous retrospective study.

A published just in the last couple of years, there was a reported 17% mortality rate, a lot of which was associated with the underlying IMPA. So we often, I've previously at least thought about IMPA as being, you know, one of the least severe immune mediated disease when we compare it to ITP and IMHA. When we think of those patients who can be profoundly unwell and hospitalised in an ICU requiring blood products and round the clock care, you know, and I've always thought about IMPA as being sort of, you know, a less severe immune mediated disease.

But really when we look at outcomes, you know, mortality rates of 17% are not all that dissimilar from those that are reported in some of the studies in the IMHA. And ITP, you know, and certainly during, treatment, patients who have IMHA and ITP relapse a lot less frequently whilst they're on treatment. Than patients with IMPA, and also, when discontinuing treatment, patients with IMPA can relapse a lot more quickly than those with ITP and IMHA as this paper that I've just referenced to the right of the screen noted in 2024.

So I think the summary is that IMPA is certainly something, that you will see in primary care practise, that can definitely be diagnosed, with, you know, relatively limited sort of facilities in primary care practise, and absolutely can be managed in that setting as well. But I think you have to make sure that you're happy with your skill set to be able to perform joint taps. I think you need to get comfortable, you know, treating a few of those more straightforward IMPA patients and be aware that there is certainly, you know, a population of IMPA patients that can be tricky to diagnose, can be associated with multiple comorbidities, can be very treatment refractory, and ultimately will benefit from referral to a multidisciplinary centre for further workup and management, .

So yes, that's pretty much all there is to say about IMPA. Thank you very much for listening and I hope to see you next time.