BONUS CASE: A tricky case of chest pain that kept coming back

In this bonus case episode, Dr Roz Benson talks to Dr Nicola Heyer about an interesting case of chest pain that kept returning, can you work out what's going on?

References:

Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center | Journal of the American Heart Association

 ESC Guidelines on Pericardial Diseases (Diagnosis and Management of)

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Transcript

RB - Hi, and welcome to this BSR talking rheumatology podcast. My name is Roz Benson. I'm one of the digital learning editors at the BSR, and I'm delighted to have with me Nicola Heyer today. So welcome, Nicola.

NH - Thank you very much for inviting me. 

RB - And can I ask you to introduce yourself because you're gonna tell us about a really interesting case in a minute. 

NH - So I'm currently an IMT3 trainee. I'm working at St.George's Hospital in London, and I'm hoping to pursue a career in rheumatology. 

RB - Brilliant. So we'll get right into the case if that's okay. So this is a case which was a bit tricky and an interesting case of chest pain, really. So perhaps you could start off with telling me about how did this patient initially present?

NH - Yeah. So I'll tell you a little bit about the patient himself first. So this is a 40 year old Caucasian male, previously fit and well, so no past medical history. And, actually, his initial presentation wasn't to our services. So he had a few presentations to his local services before he eventually ended up in our tertiary center. So his first presentation was to his local emergency department, and he presented, like you said, with chest pain. And at the time when he was assessed, he felt this was pericarditic in nature. He was, however, clinically well, so he was discharged with ibuprofen and paracetamol, and went on his way. Unfortunately so I think things did settle, but then, unfortunately, things got worse. So around four weeks later, he presented again to his local emergency department, and he had recurrence of his symptoms. He had recurrence of chest pain, and this time he was short of breath and systemically unwell. So he earned himself a admission into his local hospital, and they found that he actually had a large pericardial effusion at this point. They ended up draining it sent it off was of various, testing, but he was eventually discharged with a diagnosis of presumed viral pericarditis. And at discharge, he was given some colchicines, so five hundred microgram micrograms twice a day. He'd improved, and, again, he was discharged on his way. 

RB - Okay. And so, hopefully, case solved. Everything's okay. Solved.

NH – Yep ahha that’s about the end of it. Yeah.

RB - I suspect there might be a bit more to this. So what happened next?

NH - Unfortunately, case not quite solved. So like I said, he's got better. But then this time around, eight weeks later, he ended up presenting again to his local emergency department, again, with recurrence of his symptoms. So he had chest pain, he was feeling unwell in himself, so, some general malaise, and he was also feverish. He was reviewed in his local emergency department. They gave him some tramadol and discharged him home, but he didn't stay home very long. So I think less than a day later, he re presented his local emergency department, this time because he'd had an episode of syncope. Obviously, this raised some alarm bells. When he went back to his emergency department, he was feverish, he had markedly raised inflammatory markers. So because CRP was over 300, slightly raised white cell count, he was tachycardic. And because of concern about, you know, pleuritic or procarditic chest pain, and syncope, they ended up doing CTPA. And, fortunately, they didn't find a large PE, which is what they were looking for. But they did find that, pericardial effusion had recurred. This time, it was large. There's also left pleural effusion and this is how he ended up in our center. So, the hospital I work in, St. George's, is a tertiary cardiology center so he was, transferred there for emergency pericardiocentesis. 

RB - So I think he went on to have a pericardial aspiration. Is that right? 

NH - So actually the pericardial aspiration was from his first admission. So there was a plan for a pericardial aspirate, that's the reason that he was transferred but the cardiologist, you know, did that they re echoed him. And I think from my understanding, it was quite posterior, they didn't feel they were able to get any fluids. So what ended up happening was, you know, obviously, fluids can be, really helpful, in your diagnosis here. So two things happened. So first was, we asked for some information from his local hospital so we got the results of that previous pericardial aspirate that he had and also, like I mentioned, there was a large left sided pleural effusion. So we asked a respiratory team to come and they aspirated that. 

RB - That's quite a helpful tip there, isn't it? Because not everybody is ok with, pericardiocentesis or pericardial aspirates, are they? but, actually, sometimes you can get fluid from different places. 

NH - And, actually, it was really helpful. So I think, I'm an IMT3, so I work as a medical registrar. And often, you know, when you're thinking, but take if you had someone with fluid in multiple places, the first thing I'd be thinking of is something like heart failure but actually, when you look at the aspirate results, both of these were exudates, so they both had very raised protein levels. Whereas if you're thinking about more of a diagnosis of heart failure fluid overload, you wouldn't expect that. You'd expect it was a transudate. So I think this also gives you a bit of an idea, you know, thinking expanding that die like, your die a differential diagnosis and thinking about other sort of inflammatory causes. 

RB - So the white cells are really helpful, aren't they? And the protein and the well, the protein particularly about whether it's exudate or transudate. And then the white cells are also looked at and then what are some of the other things that we look at within the pericardial aspirate to try and help with diagnosis? 

NH - Yeah. So I think it's also so if we're thinking about other inflammatory causes, it's really thinking about how different you know, is it autoimmune? Is it infection? Is it malignancy? So certainly, both pericardial fluid from the previous admission and the pleural fluid had been sent off for culture. It didn't grow anything. It was also sent off for TB cultures again, this was negative and cytology was performed and, again, was unremarkable. 

RB - So I guess at that point, you probably did you feel quite confident this wasn't infection causing this? 

NH - Yeah. So, I mean, he had a very extensive investigation. So being at a tertiary center, have access to an infectious disease team and if you look at the list of different tests that were run, you know, we pretty much looked for absolutely everything from the, you know, obviously setting things up for culture, doing respiratory viral panels, etcetera, to the weird and wonderful. And it all came back negative but I think at this point, actually, clinically, he'd improved. So he'd had a course of antibiotics, he'd been started. So I think, he initially was on some colchicine, the cardiology team had added in some high dose aspirin and his inflammatory markers settled he got better himself for pericardial effusion on discharge. He'd had a repeat echo, and this had resolved. So I think pragmatically, it was felt that they'd ruled out anything sort of worrying like an infection, malignancy, and he was discharged home. And I think it's actually quite interesting if you read the discharge diagnosis on of a discharge summary so it says the diagnosis is likely viral pericarditis with superimposed bacterial infection with recurrent pericardial effusion query cause unclear. So I think you kinda get a sense from this, you know, reader base. You kind of get the sense that they didn't really know what was going on, they didn't have a definitive diagnosis. They sort of still put their money on this thing. The most common cause of pericarditis, which is viral. 

RB - And so, and that's often the case actually, isn't it?

NH - I don't think is you know, I think that that's a reasonable approach, and I guess it's just with these patients thinking about having some follow-up.

RB - Yep. And having the open question is there anything else which could be positive in this situation? And so heading back to the case, what happened next?

NH - Yeah. So unfortunately, once again, he didn't stay at home. So he re-presented and this is his fourth presentation. Again, he had an episode of collapse, he had recurrence of his chest pain. He was pyrexic and those rose inflammatory markers, which had really nicely settled on his previous admission, were back up in the two hundreds. So CRP was, in the two hundreds. So he's readmitted again under the cardiology team at our center, and he had a repeat echocardiogram, which showed, again, a little bit of pericardial fluid and then also some, thickened pericardium as well. So some evidence that there was some ongoing inflammation, potential, some longer term changes there. 

RB - And so we've got some cardiac imaging happening with the echo. And then, obviously, you've talked through some of the more basic blood tests that we might do when you come into hospital and you've got an infection fever but what were the results when you did some immunology on him? 

NH Yeah. So he actually had quite, again, quite extensive immunology panel sent. He had an ANA, DNA, double stranded DNA, had anti phospholipids panel. He had a, I think, a ferritin, which was mildly raised, anti CCP, rheumatoid factor. Again, all these came back as negative. 

RB - And, actually, all of those tests that you've recommend that you've just talked through are, would be recommended ones that you'd potentially do in somebody who's had a recurrent pericardial effusion with no clear cause. 

NH - So if you're looking for a so the EFC guidelines, so the European, Sensitive Cardiology, that's what they recommend. Yeah.

RB - And so, I think you also had a ferritin as well performed as well is that right?

NH - Yeah. So I think his ferritin, was just mildly raised, I think it was 800 or about something around that. So if we're thinking about other sort of auto inflammatory conditions like still adult onset stills or, you know, the more extreme sense thinking about HLH So we didn't feel that was the case. No. 

RB - No. You'd expect it to be quite significantly higher, wouldn't you, in that sort of situation? So, with all these blood tests, lots of things coming back negative. What was the clear evidence of active inflammation ongoing in the echocardiogram and then the recurrent presentation? What was the thinking now? Was there any further thoughts regarding a diagnosis?

NH - So, yeah, it was actually at this point that he was referred to the rheumatology team. So at the point of referral, he already had quite extensive workup, and he was seen and the diagnosis that was suggested was that of idiopathic recurrent pericarditis. So we can talk a little bit more about this, but essentially thinking about this maybe more being an auto inflammatory condition, rather than an autoimmune condition. And there was a decision following MDT discussion, to trial him on anakinra. So he was following he had, I think, a a few days of, prednisolone to bridge while we were getting access to medication, we started on anakiniran actually had a really remarkable response, both so in terms of his inflammatory markers, his symptoms, and then also with repeat echocardiograms of resolution about effusion and those, changes that we've seen previously. 

RB - So and just for my understanding, did he go home on the colchicine in between his admissions and then pericardial effusion developed despite being on colchicine? 

NH - Yeah. So he had been consistently on so I think he had probably a month or two of colchicine because he was started on that first admission at his local hospital, as well as high dose aspirins. I think he was on a good going dose, nine hundred milligrams three times a day, which is, you know, really, really trying to suppress what was there, but still was presenting again and again. So that was the argument for giving him, you know, trying to change tack and, the argument for giving him Anakinra. 

RB - Which isn't always straightforward to get in terms of funding, is it? Because we don't have an NHS commissioning policy for this as yet. 

NH - So I think even, you know, even working at a tertiary center, we were able to start it initially, but then ran into some problems of ongoing funding. So I think there was there was an attempt to switch him to I think he was try we tried to switch him to Azathioprine, as an alternative, but he ends up flaring again. So he's switched back to Anakinra and referred to the, National Centre at Royal Free, where they've been able to continue the anakinra, and he hasn't had any further flares, essentially. 

RB - A very positive outcome for this young man, really, who was having significant impact on his daily life in these problems. So, you've you've told us what the diagnosis was that it was felt to be an idiopathic recurrent pericarditis and treatment was started. But can you tell us a bit more about what does what is idiopathic, recurrent pericarditis IRP?

NH - Yeah. So I think there's two ways to think about this. So the first is, you know, what it says on the tin, so idiopathic recurrent pericarditis. So about recurrent parts, if you look at some EFC guidelines, this is thinking about having a further episode of pericarditis after you've had a symptom free interval of at least four weeks. So certainly in our gentleman, he fulfills this on multiple occasions. Actually, recurrence isn't uncommon. So I think, up to thirty percent of people, they have recurrence and most of these is idiopathic. And then really thinking about the idiopathic thing, it's about all those variety of investigations that he had. So making sure there's no alternative explanation had. So making sure there's no alternative explanation as an underlying cause. Then I think the other way to think about this is, is what I mentioned about, is this an autoinflammatory disease? So I know there's increasing sort of thought that actually pericarditis is an IL1 driven process. So it's thinking about it more as an auto inflammatory condition so by that, I mean, a condition that's driven by the innate immune system where we don't have any identifiable extrinsic trigger. There's no sort of underlying autoantibodies or t cell driven process, that's, initiating the inflammation. So often we think about so I think in the rheumatology sphere, we often when we hear about autoinflammation, we think about those rare monogenic causes, like familial Mediterranean fever but, actually, I think we're getting more evidence that there's potentially a spectrum of auto inflammation and autoimmune disease, and those monogenic causes are the extremes and actually, there's all this grey area in between, where there's, autumn inflammatory, autoimmune conditions, and potentially some overlap between the two. 

RB - That's very helpful. So clearly thinking about the immunology behind it and it being an IL1 driven disease was then the driver behind thinking why anakinra might be a good choice.

NH - So I think actually, part of this has been we found that colchicine which interrupts IL or, you know, one of its, mechanisms is interruption of IL1 signalling. So I think that's where this has initially come from. It's the effectiveness of colchicine and then thinking about how we might build on this and finding that actually specific interleukin one blockade is really effective. 

RB - And my understanding of these types of conditions is that actually colchicine can be used at higher doses than we might typically feel comfortable with in prescribing for our gout patients. 

NH - Certainly not something I'd be doing, but I know having heard, professor Lachman talk about this, I think she is a bit more liberal with the colchicine use.

RB - Yes and with good effect as well. So it may well be that if we are stuck with a patient like this that we are unable to prescribe anakinra for, there is some movement in terms of dosage of colchicine as well.

NH - I think it's made you limited by site so it's like those side effects are mainly limited, isn't it? Yeah.

RB - Because diarrhea can be really really problematic for some people, can't they? So can you tell me a bit more about IRP and what we what we know about in terms of, the genetic, predisposition for it? 

NH - Yeah. So I think it's going back to that thing that I mentioned about sort of monogenic versus polygenic. So I think there's a study from Peter Tal, from professor Lachman's group, back in 2022. And, certainly, we know that we've identified certain genes like MEFV that underly familiar, you know, familiar Mediterranean fever, etcetera, that certainly drive for monogenic causes. But for most, increasing thought that IRP has a polygenic process, poly underlying polygenic mechanism. And I know in their study, looked at potential deleterious variants and found that, actually, there's increased frequency of, a deleterious variant with MEFV one, in those patients. 

RB - Okay. So, obviously, IRP is an is rare, not something that we would necessarily come across. But, we've talked about potential treatment pathways, looking at IL1, colchicine, the addition of anti inflammatories. And then what our top choice drug potentially might be would be anakinra in these situations. But, actually, in discussing the case, you talked about just the general approach to pericarditis because that's something that we probably don't uncommonly come across on the medical take or as a referral. So can you just talk us through a bit of a systematic approach to a patient pericarditis? 

NH - So I think, the ESE guidelines are really helpful in this. I think maybe one thing to say is, the current guidelines are published in 2015. We're currently recording this in 2025. And I know that there are new guidelines that are immediately being published. So, what I'm going to be talking about is based on our most up to date guidelines, but might be worth if you're I think they're planning to publish them in August. It might be worth having a look at those, if you're listening to this, after that date. So essentially they say they acknowledge that actually the majority of pericarditis is viral. So the vast majority has a benign course. They recommend that we don't do extensive screening in everyone, but there are certain patient populations where they suggest and certainly think we're thinking about people who might be referred to rheumatology. I think this applies so it's anyone who might have suggestion of, under alternative underlying etiology. So I think potentially people who might get referred to rheumatology. And then it's also just, patients who have features of, potential poor prognostic features. So these this is really anyone who's got a large effusion. Certainly, if they've got tamponades, you want to be thinking about if there's an alternative cause. There's also patients who have quite a marked inflammatory response so if they've got fevers, and if they're not responding to initial treatment. So it's really those patients like this patient who was started on colchicine, started on NSAIDs, but still ended up representing and having recurrence. Yeah. 

RB - So these sorts should raise red flags and actually the import highlights the importance of taking a really thorough history if that patient presents and you're the admitting doctor because you might pick up some subtle signs of potentially underlying or term issues 

NH - or points you in the direction of actually need to think a little bit more and not just saying that this is viral. Going back to those EFC guidelines, they have a really helpful table, which is, I found, really useful to think about what those potential underlying causes can be. I think it's also important from a rheumatology perspective to consider that after viral being the most common, the second most common is autoimmune disease. So really keeping that as, you know, especially most patients with recurrence, keeping that as, a differential is important. I think in our center, we did one study, looking at these patients who, had recurrence and actually how good are we at screening them for underlying rheumatological causes. We found that actually in patients with, you know, not their first presentation with patients who had recurrence, we only forty one percent of our patients had had an autoimmune screen and when of the patients that had had an autoimmune screen, sixty percent of these had a positive ANA. Obviously, these are quite small numbers, but, and of the ones with positive ANA, I think a couple of them had positive ANAs as well. So it's really important. Yeah. Yep.

RB - Absolutely. And if we don't test, these are unknown unknowns, aren't they, as to whether or not there could be a an autoimmune driver. 

NH - Yeah. So I think part of it here is also about developing that relationship with, acute medical colleagues, and being open to seeing these patients as well and having that line of communication is really important. And actually, as is well recognized, it's it can be difficult to interpret immunological tests if you don't do this in your day to day job as well so trying to understand whether actually a weekly positive ANA is of significance Yeah. In these sort of situations, a conversation with, between specialties and an understanding of any other, extra cardiac manifestations can actually be a big deal. 

NH - I work a lot in acute medicine. It's really busy, and not everyone has an understanding of what might you know, the questions that you need to ask. I think it goes back to that, you know, taking that really thorough history. So often having that input from rheumatology can be really helpful.

RB - Sounds like a good table to have a look at it and try and commit to memory or at least know where to find it when you're on call. So in this particular case, obviously, we talked about this autoimmune screen, but what other pointers were there that idiopathic recurrent could be the diagnosis?

NH - Yeah. So it so first thing, it fulfills the idiopathic. It fulfills for recurrent. But actually, it's a little bit more than this as well. So it's about having that it being coupled with that systemic inflammatory response. I know going back to that study that I mentioned from professor Lachman's group, they looked at sort of presenting features, and they found that patients with IRP often so they obviously present with pericarditis, but they have a marked systemic inflammatory response. They have a very raised CRP. They might be pyrexic. And, actually, having extra pericardial effusions is often a feature. So if we think back to, our patients, he also had a pleural effusion. So certainly, that fits with this being IRP. I think one thing that's quite interesting is that this is often different from when we think about those monogenic, systemic or inflammatory diseases. I think often we think of pericarditis, you know, as potential features. And they can be a feature, but they're not often presenting feature or the predominant feature. So really when you got someone with pericarditis, you're thinking about is this IRP.

RB - That's really useful. And so, actually, I think it probably the diagnosis was made fairly quickly, wasn't it, in this gentleman?

NH - Yeah. I mean, he did have a a few a few admissions, but I think there are patients who go for years and years with recurrent pericardial effusions, not people not really knowing what to do with that.

RB - Absolutely. And I think probably as our awareness, increases about this condition, particularly as rheumatologists, it can help lead to that diagnosis being made quicker. And so, can you just talk us through the general approach to management in ILP? We've slightly touched on it

NH - Certainly, we've mentioned, you know, that initial approach and that was what happened in our patient. He was so the initial approach is really about giving, NSAIDs, so either high dose aspirin and like I said, that's not seventy five milligrams once a day, that's a whopping nine hundred milligrams, three times a day alternative being ibuprofen, and given this with colchicine. The, EFC guidelines suggest a dose of five hundred micrograms once or twice a day, based on weight. I think it'd be interesting to see if there's any changes in that of the new guidelines. 

RB - Yes. Absolutely so watch this space in time. 

NH - Yeah. I think really the evidence of I think the key here is with colchicine is where the evidence is. So I think there's been three different trials, looking at the impact of colchicine on recurrence. And, across these trials, we know that it actually reduces risk of recurrence by almost fifty percent. So quite a significant, significant reduction. So it's really important that these patients are on culture scene. 

RB - And sometimes, of course, we use steroids in our patients. Yes. Or very often we use steroids, although we try to minimize their usage. Is there a role for steroids in this condition? 

NH - So from my understanding, so we try and avoid steroids. So, referring back to that study by professor Lachman's group, I think there's lots of evidence of this as well, but actually, corticosteroids don't help. And they're associated with potential risk as well. I mean, we're very familiar with, sterotoxicity in rheumatology. This is these patients already have some cardiovascular risks. So, you know, giving them steroids on top of that, especially if they're not helping, is, that risk benefit, it doesn't really, help with that. And actually, there's evidence that patients who are given steroids in IRP are more likely to have recurrence, and they're more likely to have chronic fatigue. So it's not just about they don't do anything they potentially cause harm.

RB – That’s a really good point to make

NH - It’s not an uncommon question that, acute medical teams or even cardiology teams might ask. And if you look at again, looking at that study, they found, I think, over fifty percent of those patients, and this is at the National Center, were on corticosteroid. So it's not an uncommon practice as well. So I think it's really important to be aware of that. 

RB - So really, what we'll do is we'll link to that paper in the show notes if anyone wants to read it in a bit more detail. So, thank you very much, Nicola, for bringing and explaining so beautifully a quite, not an uncommon case, but actually a diagnosis that we might not, commonly think or make, and also the approach to management. So, are there any particular take home messages that you would want to share with the listeners? 

NH - Yeah. So I think, certainly the things that I learned from this, case is, firstly, about IRP and thinking about it being an auto inflammatory condition. So it certainly changed how I think about pericarditis, having an awareness of those, things that we need to rule out, so particularly thinking about autoimmune causes. And then I think it's about, the idea about interleukin one and the concept of focusing treatment on that. So culture scene certainly, but then, thinking about more targeted therapy, so, you know, anakinra, as a potential management option. 

RB - So one of the things for me which has been really useful in the discussion of this case is the role of the or the lack of the role of steroids in the management of these patients and actually the potential it could be deleterious in in their outcome.

NH - I think it's so important to have awareness of because it's so easy to go ahead and prescribe that because it's something we use so commonly, isn't it?

RB - Yep. And it's so much efficacy actually in many other, auto inflammatory driven conditions, but actually, this seems to not be the right drug.

NH - Yeah. So it's knowing what alternatives it isn't it? Yeah.

RB - Absolutely. So thank you very much for speaking to us about this. And, if you've enjoyed us into this podcast, have a listen to some of our other BSR talking rheumatology cases.