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Allan Klein: My name is Dr. Allan Klein. I'm a professor in medicine at Cleveland Clinic, and I'm the director for the Center for the Diagnosis and Treatment of Pericardial Diseases. I'm delighted to have my panelists, Dr. Paul Cremer, Paul, associate director of cardiovascular medicine training program and cardiac intensive care unit, and Dr. Imazio, all the way from Udine, Italy, who's the head of cardiology, contract professor of cardiology, Cardio-Thoracic Department. He's also the chairperson for the European Society of Cardiology Working Group on myocardial and pericardial diseases. Welcome, Dr. Imazio. And finally, we have Dr. Brittany Weber, director of Cardio-Rheumatology Clinic, associate physician at the Brigham and Women's Hospital. So we have an excellent panel.

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We have a very exciting agenda. I'll be talking about where are we now, current knowledge gaps related to management of pericardial diseases. Dr. Imazio will cover treatment advances in pericardial diseases with interleukin-1, reviewing the totality of the data. Dr. Imazio has to leave early to catch a plane. We can ask a few questions after he's done.

 

And then Paul and then Brittany will show some cases of recurring pericarditis, some challenging cases. And finally, Brittany will end up with the How Do We Apply IL-1 Inhibition in the Management of Pericarditis? And at the end, we'll have plenty of time for discussion.

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Before I get going, so why is pericarditis important? A little anecdote, last night, I was at a restaurant with Dr. Imazio, and we took an Uber. The Uber driver seemed to have some medical knowledge. He says, "Are you cardiologists?" So I said, "Yes." And he says, "Is it true that COVID and the vaccine cause mild pericarditis?" I looked at the guy. I said, "Do you know who you're talking to? We have the world's experts in this Uber. We have Dr. Imazio from Italy and myself." And Dr. Imazio gave him an explanation how COVID causes inflammation. It must be important, if the Uber driver is current on pericardial disease.

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There is a major interest in pericarditis. I say that there's a new renaissance, because now we have the diagnosis, and now we have the treatment. And there's an explosion of publications. If you look on this slide, this is just a sampling of IL-1 inhibitors for recurrent pericarditis. And then thinking back two years ago, around this time, I was in my house, doing a virtual, a basic, a lead-breaking trial in RHAPSODY, so literally two years ago. And here we are, two years, fast forward, of the excitement of this field.

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These are some of the IL-1 inhibitors that we'll be talking about: anakinra, which is a recombinant IL-1 receptor antagonist; rilonacept, IL-1 alpha and IL-1 beta trap; and canakinumab, which is human monoclonal antibody for IL-1 beta.

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Another major advance is in advanced imaging, how advanced imaging, advanced echo with strain and particularly CMR is very, very important. This is a picture of a late gadolinium enhancement of a patient, a 17-year-old boy with rip-roaring a recurrent pericarditis. And from this picture, from this, the intensity of the late enhancement and how circumferential it is, at the different level, will predict how long you'll have to treat the patient. So when I see something like this, I tell them that this is going to be more than a year, maybe between three and five years of active therapy. So this a good imaging phenotype for these patients.

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The other important note is about there's a spectrum of pericarditis. Pericarditis, on the top of this slide you can see ongoing inflammation, and then the bottom, in yellow, is constrictive physiology. So when we examine our patients, we see where they are on this ladder. For example, you present with acute pericarditis. You may have edema and delayed enhancement, and you may have transient constrictive physiology. And then you go down the line. Then you have recurrent, then chronic, then burnt out. You can see the constriction evolves, as well. And at the bottom, you can see the MRI of edema and delayed enhancement, and over time, it disappears. And then the treatment in the purple, you can see a triple therapy, NSAID, colchicine, steroids and/or biologics, and eventually, it's burnt out where you need surgery.

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Let's talk about pericarditis, in general. It's probably the most common disease of the pericardium. Roughly, there's 27.7 new cases per 100,000 per year of acute pericarditis. Most of the time, we don't see them as cardiologists. The ER physician may see them. But there could be significant risk of complications and recurrences.

 

What is the most common cause of acute pericarditis? Well, in our practice that we see in different hospitals in Europe and North America, the most common cause would be viral. It doesn't matter which virus. And the other thing, we don't know the cause. It will be idiopathic. Sometimes their lumped together, idiopathic/viral.

 

And a leading cause, now, is post-cardiac injury. Now, anybody from electrophysiology in the audience? No EP? Usually there's one person that raises their hand. I said you're my best business because ablation, whether AFib ablation or BT, pacemakers is a cause. And then, Brittany is involved with cardio-rheumatology. A lot of lupus patients and rheumatoid arthritis patients may come, as well.

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Now, these are the 2015 ESC guidelines, and this is their criteria. Let me put a little note that ACC and AHA don't have a current guideline. We use the European guideline, and they're one of the leaders. This is from 2015. This is how you divide the patients, acute, incessant, recurrent, chronic.

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Let's talk about acute. Acute, you need two of four clinical criterium. You need pleuritic pericarditic chest pain, which is sometimes quite vague. Patients do have different things they may say it hurts when they breathe. So I'll point out some of the limitations. A rub, now rubs are hard to hear. If you're not actively inflamed, you're not going to hear a rub. EKG changes, quite classic, but there's a lot of young people with pericarditis... or no, there's a lot of young people that don't have pericarditis. They have physiologic ST elevation. And finally an effusion, You would think it's simple, new or worsening, but people mix up some of the, next to the RV, the fat next to the RV, and they call that effusion.

 

This is what we use daily, two of the four criteria. Now, objectively, you have to look at CRP, which comes in two forms, the regular CRP or a high sensitivity and the sed rate and WBC. And more objective would be the pericardial inflammation by MRI or CT, but MRI has to be in good hands. You have to know what protocol is a pericarditis-type protocol to give. These are the criteria, two of four.

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Now, then we divide it into incessant or recurrent. Now, we're talking a lot about recurrent. That means that you have acute pericarditis and you go on the medicines, and then you get better for four to six weeks, so it disappears. It gets better. Then probably, as soon as you taper, it comes back. That what we call recurrence. Patients don't tell you they have recurrent. You have to dig it out in your history.

 

Incessance is a little more aggressive. That means for those three months, you're in that acute stage. It's basically non-stop, and these are a little more aggressive. And finally, after three months, it becomes chronic.

 

This is the ESC guidelines. We're working to do a white paper, a consensus statement in the US, and Dr. Imazio's talking about something similar in Europe. He's the chair of that task force.

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This is from Dr. Cremer. Who are these pericardial patients? So we mentioned 27.7 new cases per 100,000 per year of acute pericarditis. Roughly 5% of nonischemic chest pain in the ED is pericarditis, but most patients with acute pericarditis, we don't really see. They resolve. The ER physician treats them. Roughly a couple percent end up in tamponade. On the other side, 15% may have some type of elevated troponin and have some myocardial involvement.

 

But we're really interested, in this audience, is what we call complicated pericarditis. This is a term Paul coined, and they are complicated. They're not straightforward. Roughly, a third of the patients become recurrent. And a subset of that have multiple recurrences. And these are the things that we see in our practices in the US and Europe.

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Then there's a group that develop constriction very early, a so-called transient, or reversible constriction. You see inflammation. You see some of the heart failure, the septal bounce, respirophasic shift. And then, on a couple of percent will end up with chronic calcific constrictive peri. This is the landscape that we see.

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How about recurrent pericarditis? Recurrent pericarditis, you don't die from recurrent pericarditis, but you have a lot of morbidity for this that impacts patients and the healthcare systems. They keep on coming back. They have a lot of phone calls, messages. I think we can all attest to that. And that talks a little about a pericardial center. How do we handle all this influx of calls, how to handle if you're... Should I take the vaccine, the booster, or not take the vaccine?

 

How many patients? Well, the data out there suggests there's a huge significant... I mean, a clinical need. There's a big educational gap for patients and physicians and cardiologists about this field. Roughly, I would say 40,000 patients in the US are seeking treatment annually for recurrent pericarditis. This could be more or less, but roughly, that's the number. And as we mentioned already, roughly a third of the patients, after the acute episode, will come back within 18 months.

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What are some of the causes? Once you get the acute attack, what's the biggest causes of recurrence? Well, the biggest cause, as we learned from Dr. Imazio's papers, is that you don't treat the first episode very well. As I showed that MRI slide of how long, it could take three to five years, and you're giving NSAID for a week, or colchicine for 10 days, so it's definitely going to come back. Or you go to the ER and they give you a dose pack for a week, and as soon as you stop it, it comes back. These are some of the inadequate treatment of the first episode. And/or you have a very aggressive case, you're not responding to the NSAID and colchicine and, oh, it come back.

 

The CRP is very, very high. We have somebody in the hospital with a CRP of 400, so you can imagine some of those findings, high CRP. And finally, you have to remember, for idiopathic, the pathophysiology is auto-inflammatory. We're going to hear more from Dr. Imazio about the auto-inflammatory cascade, and how IL-1 blockers can targe this cascade driven by IL-1.

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This is the current algorithm from the ESC, how to treat. On top, you can see acute pericarditis, and the bottom is recurrent pericarditis. As we talked about the definition, you need two of four clinical criteria. First line, everybody knows is dual therapy. Basically, you tell them to go on an NSAID, often ibuprofen. It could be indomethacin. For older patients with CAD, aspirin will be the way to go, these are not small doses, these are big doses, and colchicine.

 

But the biggest thing, the biggest fudd I have with patients, or the biggest dilemma, is you tell a 35-year-old person that likes to go to the gym that they have to limit their exercise. This is, for active inflammation, this may not be a good thing. We have to think, on one side, we want to treat the disease, but on the other hand, if you ruin their optimism by not going to the gym or working out, that's the big thing. And there's some debate whether, on IL-1 blockers, whether you can exercise. How do you look at that exercise piece? That's a good point for discussion for future research.

 

First, if you fail first line, and then you go to second line. Traditionally, it's low-dose steroids. And Dr. Imazio has shown roughly it's a half a mg per kilogram of steroids. But mistakes out there, patients are getting put on 80 of prednisone or 60 of prednisone. I see some teenagers with moon faces, cushenoid, buffalo hump, so the clinician is not too familiar with this.

 

Then for recurrent, it's similar. As I mentioned, you need to get better for four to six weeks, then it comes back. And then first line and second line are the same. And then third line is things that rheumatology may often give, Imuran, azathioprine, the biologic, anakinra, rilonacept, IVIG, methotrexate, other things, and finally, a pericardiectomy. Now, as you'll see, this algorithm will be changing.

 

Let's talk about steroids. Now, steroids has a bad rap, but it is to treat autoimmune, let's say lupus and rheumatoid, a lot of side effects. A lot of side effects, cushenoid, cataracts, osteopenia, osteoporosis. When you give it and you take it away too soon, you have a lot of recurrences. We are doing a project about the association of steroids with all the complication. And if you go on steroids, don't taper within a week or 10 days. Go very, very slow with this. But there could be a role for steroids, and then we mentioned about the other therapies.

 

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Now, perhaps the newer algorithm, we'll talk about this, is instead of steroids, should we go to the IL-1 receptor antagonist? This may obviate the second-line therapy with steroids. This hasn't been formally tested, but this may be another approach, and a lot of us may be adapting this for the future.

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Why is there inertia, clinical inertia in the diagnosis and treatment of recurrent pericarditis for clinicians, in 2022? As I mentioned, two years ago, we presented the RHAPSODY trial. This is two years later. First of all, people don't apply the guidelines very well, objectively. Once again, perhaps they're mixing up some of the clinical criteria, but perhaps what we should do, in good hands, a good CMR, check CRP, look at an echo very carefully, and become very good clinicians, take a good history.

 

What are some of the difficulties in treating multiple recurrences? Well, as I mentioned, you're under-treating it. You're giving colchicine for a week and NSAIDs for two weeks, roughly. You're giving prednisone and taking away too quickly. And ER physicians have to be educated not to do that.

 

We have to understand that there's an inflammatory phenotype. So when you look at the patient, is there a lot of inflammation? Is the CRP high? Is the MRI very inflamed? Or there's no inflammatory phenotype. But a lot of the inflammatory phenotype is driven by this auto-inflammatory cascade, which Brittany and Massimo will talk about.

 

And there's been a slow adoption of IL-1 blockers in steroid-dependent colchicine-resistant patients. A lot of cardiologists, when they hear about this biologic, "That's a rheumatologist venue," but I think it's inflammation is getting into the cardiologist realm. We all have to learn. Our nurse practitioners, our nurses have to learn how to handle this, how to handle any complications with pharmacy to bring this to a fruition.

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I want to thank you for your attention, and we'll move on. Thank you.

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So now, let me introduce my European colleague, Dr. Imazio.

Massimo Imazio: Thank you very much. Thank you very much for the invitation and the opportunity to discuss with you the treatment advances in the treatment of recurring pericarditis.

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I will start with this polling question. First of all, there is no right answer. It's just to test your opinion on this topic because is different in Europe and US, so the prescription condition is also different.

 

When do you consider an anti-inrterleukin-1 agent for the treatment of pericarditis? In patient with acute pericarditis after failure of non-steroidal anti-inflammatory drugs, in patient with recurrent pericarditis after failure on non-steroidal anti-inflammatory drugs, in patient with recurrent pericarditis, but also after failure of a NSAID plus colchicine, and in recurrent pericarditis after failure of non-steroidal anti-inflammatory drugs, colchicine and corticosteroids?

 

The winner is what an European colleague would do because, for instance, for me in Italy, I can make the prescription of an anti-interleukin-1 agent only after failure of all conventional treatment, including non-steroidal anti-inflammatory drugs, colchicine, and corticosteroids. In Europe, we can apply for this treatment in patient with recurrent pericarditis, corticosteroid dependence and colchicine resistance. But in the US, you have the opportunity, really, because rilonacept is a FDA-registered drug for recurrent pericarditis to use this drug even before corticosteroids. This is an option that you really have to consider.

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Let's move on and see, so what is the role of interleukin-1? As we know, interleukin-1 is one of the most active and important pro-inflammatory cytokine. We know that when there is a pericardial damage, the injury, the pericardial start releasing interleukin-1 alpha. Interleukin-1 alpha is another mean that triggers the activation of inflammatory cell, especially tissue macrophages, and activates the inflammasome, a complex of protein that is generated in pro-inflammatory states.

 

Colchicine is a nonspecific inhibitor of the inflammasome because it is able to block the assembly of the inflammasome. And the final result of this activation is the production of interleukin-1 beta because that strong for inflammatory cytokines responsible, as you can see, for the induction of interleukin-6 and the elevation of CRP. This is important because if a patient with recurrent pericarditis has elevation of CRP, this pathophysiology is on, and so this is the patient that probably will respond better to this kind of treatment. You can see, also, that interleukin-1 beta is responsible for fever and for pericardial inflammation. So as you can see, it is important in this inflammatory cycle, to have an antagonist with both interleukin-1 alpha and interleukin-1 beta.

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As you can see, here, you can see in this picture, the possible anti-interleukin-1 antagonists that you can find in clinical practice. Canakinumab, you know canakinumab from the CANTOS trial, is a monoclonal antibody targeted at interleukin-1 beta, so essentially is able to interfere with interleukin-1 beta, but not interleukin-1 alpha. Rilonacept is a drug that neutralizes [inaudible 00:21:35] interleukin-1 alpha and beta. And anakinra is a human recombinant form of the natural antagonist of interleukin-1, and it is so able to compete with both interleukin-1 alpha and beta.

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So essentially what we have, so anakinra is used off-label. It is not FDA approved in the US, but is reimbursed in some European countries, such as in Italy. So if you have a patient with recurrent pericarditis, corticosteroid dependence, colchicine resistant, you can make a therapeutic plan, and the drug is given for free by the National Healthcare System. And it has been included in [inaudible 00:22:17] based on some historical experience, but also in clinical trial, the AIRTRIP trial that I will show in the next slide.

 

Canakinumab has not been formally studied in the patient with recurrent pericarditis. We have a number of cases reported as case serious, but as you can imagine from what we have learned before, it is not so efficacious in patients with recurrent pericarditis. It is not really able to control the disease because the inhibition is essentially targeted at interleukin-1 beta and not interleukin-1 alpha. That is very important with patient with recurrent pericarditis.

 

Rilonacept is an interleukin-1 alpha and beta trap. It is FDA approved. We know the result of the RHAPSODY trials. It can be used in patient with recurrent pericarditis in adults and also in children of 12 years and older. It can be used in a patient with recurrent pericarditis even before the use of corticosteroid. This is very important for you, in the US.

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This is the results of the AIRTRIP trial that was the first trial that was they tested, specifically, the efficacy of an anti-interleukin-1 agent in patient with recurrent pericarditis, corticosteroid dependence and colchicine resistant. You can see a dramatic reduction of the risk of reccurencies in patients with anakinra. Their recurrence rate was 90% in those treated with the placebo and less than 20% in those treated with anakinra for a treatment duration of six month, only six months.

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These results were also confirmed in an International Registry of Anakinra for recurrent pericarditis that included more than 200 patient in Europe, North America, including the US and Canada. And you can see here, the main events, before and after the use of anakinra. You can see a dramatic reduction of the events per year per patient, considering the recurrences, from 2.3 recurrences per year before the use of anakinra to almost zero, and also dramatic reduction of the emergency department admissions, the hospitalizations, so with a impressive reduction also of management cost of these patients and the reduction of the number of patient on corticosteroids, 80% in the beginning, and after, 27%, with the use of anakinra. So very good result.

 

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What we also learned, there's other lessons that we learned from the IRAP registry is that the treatment duration is important. If you have a treatment duration of less than three months, you will have more recurrences, and the tapering for anakinra that is given with a daily injection is important because you can see that if you have no tapering, you will have more recurrences. If you have a tapering of at least three months, probably this patient is better. This is important because, today, we presented the results of the RHAPSODY, the longest sanctioned treatment. And I will show you that duration of treatment is very important for this patient.

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Here, you can see the dramatic results of this drug. You can use few injection of anakinra, a couple of injection, to have a good control of symptoms. For rilonacept, you have a weekly injection, and you can see that you can have dramatic results in five days for the control of pain, and within one week for the control of CRP. You can see that these result are maintained during the treatment.

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And here, you can see, also, the primary efficacy, and point of the RHAPSODY trial, you can see that, essentially, with this drug, you are really able, with a weekly injection, to have the full control of the disease for in the long term, and you have very good results.

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We have a very high proportion of patient who are able to maintain a clinical response more than 80%, also to have a absent of midi, mild pericarditis symptoms. The quality of life is very important and is heavily affected in this patient with the recurrent pericarditis. And you can see, also, that almost more than 95% of patients had no or minimal pain in the first weeks of treatment.

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Today, we presented the results of the prolonged treatment with rilonacept, in the RHAPSODY trial, and you could see that treatment suspension at 18 months was associated with pericarditis recurrences. So what we have learned from this lesson, these results are not disappointing, but helped us to understand that this condition is a chronic, probably an auto-inflammatory condition, so you have to consider a long-term treatment. Maybe if you have a demonstration that is really an auto-inflammatory disease, a lifetime treatment.

 

So would you stop an antihypertensive agent for a patient with hypertension directly, is probably no, and the same is for this subset of patient, very complicated patient with a lot of recurrences. You have to consider that this patient has an auto-inflammatory condition. The dramatic response to the drug is a clear demonstration that this works.

 

If you are making genetic testing in this patient, you will find that 5 to 7% of this patient with recurrent pericarditis will have a monogenic form of auto-inflammatory disease, such as Familial Mediterranean Fever and TRAPS. So this is the demonstration that there's a genetic basis for the disease.

 

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We have also, today, the presentation of the results of a patient with COVID-19 in the subset of the trial. So pericarditis and myocarditis may result from COVID infection and also COVID vaccination. Is it safe to use this drug in this setting? And you can see that this drug was quite safe and with pericarditis recurred of severity in this patient.

 

And as you know, the mechanism by which the virus is able to generate pericarditis and myocarditis is not direct infection. The virus can infect the myocardium, but is not able actively replicate in the myocardium. It's essentially an indirect mechanism because the virus is able to trigger the inflammation and to activate the inflammasome. This is a treatment for this condition.

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What about the safety? We know, essentially, that the most common side effect reported is a local skin reaction, especially with the [inaudible 00:29:14] and with the injection. You can have, also, an increase in the risk of a skin infection and respiratory infection, but severe infection, although possible, are generally...

 

And you have, although, to consider that the alternative for this patient is corticosteroid therapy, that it has more severe side effects in about 25% of patients. So we have to consider this. You can have an elevation of transaminases generally in up to 4% of cases. And in some cases of [inaudible 00:29:45] is reported, and in one to 3% neutropenia or leukopenia. Generally, the permanent discontinuation due to adverse events is limited to 3% of cases.

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So what we have learned, and I think that COVID gave us a great lesson because the pathogenesis of these diseases is more complex than a single etiology explanation. It is not on simply the virus to be responsible of these forms of recurring pericarditis. There is that interplay between different factors, including the inflammation. Some patient probably has an auto-inflammatory condition, inflammation, and an auto-inflammatory response can trigger auto-immunity. Auto-immunity can be also present in some cases. And also, the genetic component is important because there are patient that have a single episode of pericarditis with a prolonged remission, and patient with several occurrences. So you have probably to start considering a multifactor of pathogenesis. All these factors can be important, and they can be targeted for a specific treatment.

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So let me summarize that, exactly at present, we don't know the exact duration of therapy. There were current and previous studies suggest that probably you have to consider, in patient with an inflammatory phenotype, a prolonged treatment. And we add, today, the presentation of the RHAPSODY long-term extension study, showing that in such a difficult patient, a prolonged treatment should be considered. But the good news is that corticosteroid tapering is really feasible in a majority of these cases and anti-interleukin-1 agent are really helpful to help to withdraw and to stop the corticosteroids. And in specific settings, such as in the US, you have the opportunity to consider anti-interleukin-1 agent even before the corticosteroids.

 

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So a possible flowchart that can be considered, nowadays, is essentially the presentation. We are now moving towards a more targeted treatment. So if you have an inflammatory phenotype, maybe consider potential auto-inflammatory disease, the first choice is an anti-interleukin-1 agent. In the US, you have rilonacept that is FDA registered. In Europe, we have anakinra. This is the first option to consider, even before corticosteroids, if possible.

 

If you have a noninflammatory phenotype, so patient with normal CRP or lower level of CRP, probably you should consider alternative treatment. In this case, is probably low-dose corticosteroids can be an option, but there are also experiences on the use of anti-interleukin-1 agent in this patient. When the second-line treatment fails, you have a third-line option that can be represented by immunoglobulins and azathioprine and other agents.

Slide 38

So thank you very much for your attention.

Allan Klein: Okay. Massimo has to go soon. His plane is coming. So any questions for Dr. Imazio? One question, I can just start off here, very quickly, is that what do you the difference is in the treatment in the US versus Europe in terms of... It's the same patients, but what would be some of the different approaches that you see, your observation?

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Massimo Imazio: Well, the situation is essentially related to the registration. So for rilonacept, you have a FDA registration for recurrent pericarditis. This means, essentially, that you can consider this drug, even before corticosteroids. This is, I think, a great advantage you have, in the US, because it prevents the use of and limits the use of corticosteroids. On the contrary, in Europe, for instance, in my country, in Italy, you have to try all the drugs, including corticosteroids, and you can have this treatment essentially for corticosteroid-dependent and colchicine-resistant cases, so in the more advanced cases.

 

So I really invite you to consider the phenotype, the presentation. If you have an inflammatory phenotype, go for anti-interleukin-1 agent first. Maybe you can consider also the combination of colchicine because as we mentioned it before, it is a nonspecific inhibitor of the inflammasome, so you are working on the same pathway that is generating interleukin-1. So you can consider the integration of drugs. In Italy and Europe, generally you use both drug, together. This is, essentially, the main difference between the US and Europe.

Allan Klein:

One question I have is in your left side of your algorithm for the non-inflamed, the CRP is normal, and it's we're assuming they had pericarditis before they had an effusion. So the low-dose steroids, or even the IL-1 inhibitors, how does that work? What is it targeting? You're assuming it's still... There's not a lot of inflammation, but those other drugs could work. How do you look at that aspect?

Massimo Imazio:

Okay. Looking at the clinical trial, the clinical trials is that's especially the efficacy of the drug and demonstrating the efficacy of the drug in the setting of patient with a elevation of CRP. These are probably the ideal patient for this kind of treatment.

 

But as you mentioned before, and also in your presentation, you can consider also imaging. If the patient, sometimes his CRP is taken after the starting of some treatment, so maybe you will have a normal CRP because you have some treatment before.

So I, personally, think that it is very important to use cardiac magnetic resonance first because as you clearly demonstrated that they inflame the pericardium as a neovascularization, so you can see pericardial edema. You can see pericardial edema. So is we have this evidence of inflammation, and this is what we use, generally, in patient also with a new diagnosis of constriction. So, if you have evidence of inflammation, I think you can consider this treatment. I, personally, use this treatment also in this patient, even if CRP is normal, if I have a clear evidence of inflammation by imaging.

(00:36:35):

Imaging can be also the possible useful also to understand the best duration of therapy in more complicated cases. So if you are not sure to stop the treatment, if you have a typical symptom, if you want to be sure, go for a follow-up CMR to see if the CMR evidence of inflammation is present no more because you have reduction of [inaudible 00:36:59]. Maybe this can be quite useful and to develop a targeted strategy and a targeted duration of therapy for these patients.

Allan Klein (00:37:07):

So very good. Dr. Imazio is known as a world leader, did all the colchicine trials. It's a pleasure to have such collaboration on both sides of the Atlantic and try to move the field forward, together. Well, thank you very much.

Massimo Imazio (00:37:23):

Thank you.

Allan Klein (00:37:23):

Thanks-

Massimo Imazio (00:37:24):

Thank you.

Allan Klein (00:37:28):

... Massimo. Okay. Now, we're going to turn, now, to some challenging cases. Paul Cremer and Brittany will take the lead.

Paul Cremer (00:37:35):

Excellent. Thank you, Allan, and thank you, Massimo. It's great to see you, again, in person. And it's a privilege to be part of this session. I would just add, in RHAPSODY, because when we started this a few years ago, we said we really need, or now going back several years, a steroid-sparing therapy for these patients. I think part of that is, in RHAPSODY, we had a pre-specified analysis of patients who were and were not on corticosteroids. And the efficacy was highly efficacious and similar in both groups. So I think that is the clinical trial rationale for why we should be, at least in our practice, considering and interleukin-1 blocker before we jump to corticosteroids.

(00:38:20):

Usually, when we're thinking about that, as I'll show in the cases, we're thinking about someone who's going to need therapy for a prolonged period of time and have to deal with all the adverse effects of corticosteroids that Allan touched upon. The other thing that just occurred to me, it's also, in terms of the inflammatory phenotype when you're seeing these patients in clinic, to go back and look and see was there ever a point where the CRP was checked. Because it may have been, by the time they come to see you, they've had multiple recurrences, and they've been on a treatment, and then becomes very heterogeneous, in that scenario.

(00:38:50):

Okay. To start with a case, so this is a 37-year-old gentleman who had an ascending aortic aneurism and went for aortic replacement. And about 10 days after that, he got typical pericarditis chest pain, ST elevation, fevers, elevated inflammatory markers, and had a small pericardial effusion. So pretty classic, diagnosis here is quite secure.

(00:39:19):

He was treated with NSAIDs and colchicine, but continued to have symptoms and was started on prednisone a week later. This gentleman, like a lot of the patients that get referred to our clinic, every time he was tapering the prednisone and getting to a certain dose, he was having a worsening of his symptoms. And in particular, I think as Allan noted, a lot of the younger patients, exercise is important for them, and his symptoms were definitely worse with physical activity.

(00:39:47):

So I would just like to return and highlight what we think of as some of the high-risk features for recurrence in the patients who have an acute episode because they come to clinic and they say, "What's the chance of this coming back?" And we sort of say, "Okay, maybe as much as 30%." But what are the features that make that more or less likely? I think, as Allan touched upon, the fever, the marked elevation inflammatory markers, and really if it's resistant to NSAIDs and colchicine and requires escalation in therapy.

(00:40:18):

We have some high-risk features for recurrence. He comes to see us in clinic, and he's having active chest pain. This is his third recurrence. He's currently on 7.5 mg of prednisone. We talked about how therapies, in particular corticosteroids, can suppress the inflammatory response. His CRP is elevated at 66.4 mg per liter, and I think that's remarkable in someone who's also on corticosteroid therapy.

(00:40:46):

So looking at the echo, the overall LV/RV function is okay, and there's just a trace pericardial effusion adjacent to the right atrium. This was his cardiac MRI, with representative slices at the base, mid, and apex of the ventricle. What you can see there in white, nope, let me go forward here, is the late gadolinium enhancement of the pericardium.

(00:41:13):

As Massimo just touched upon, we think of the pericardium as being minimally vascular in the normal state, and part of the inflammatory response is neovascularization. So we take advantage of that, if you will, with our cardiac MRI, so that if the pericardium is taking up and retaining the gadolinium-based contrast, that's indicative of pericarditis. Also, as Allan noted, we look at the circumferential extent. This is a pretty severe case with circumferential late gadolinium enhancement at the basal, mid, and apical slices.

(00:41:46):

Based on what we know so far, what's the expected duration of treatment for the recurrent pericarditis, for this patient? I think it's sort of a theme, so far, in the conferences is, and a question that comes up a lot, clinically, from the patients, is how long do we think we're going to need to be on treatment? So what will people think based upon the case presentation, and hopefully you weren't asleep when Dr. Imazio was giving his talk-

Allan Klein (00:42:11):

Just so what'd you guys vote?

Paul Cremer (00:42:13):

A, less than six months, B, six to 12, I think C was 12 to 18, and D was greater than 18.

(00:42:20):

Okay, so actually that's good. There's a good learning opportunity here. That's what I'd like to see in our questions.

(00:42:49):

The way I would look at this case is this was a patient who would have met the inclusion criteria and would have been a good patient to enroll in the RHAPSODY trial, multiple recurrences, elevated CRP, very positive MRI. I think what we're learning is that patient, that phenotype, like Dr. Imazio touched upon, is someone who really needs a prolonged duration of therapy. Based on the evidence that we have so far, and hopefully we'll accrue more evidence with ongoing studies and in collaborations, but I think, based on what we know so far, that's someone that needs to be treated for at least 18 months.

(00:43:27):

So here, I just wanted to highlight a recent research letter that Allan led, that's in JACC, which is touching upon the prognostic value of C-reactive protein in recurrent pericarditis. We sort of know that it's helpful for diagnosis. And as I noted, it's a high-risk feature in an acute episode, but what we showed in our retrospective cohort data was that elevation CRP in a patient who's having a recurrence is also prognostically important in identifying a high-risk patient. And of note, on multi-variable analysis it were the younger patients that were higher risk, the patients who are on corticosteroids, and also the high CRP were associated with worse outcomes.

(00:44:08):

So I think in terms of high-risk features, certainly the CRP, and then the second feature to keep in mind is the pericardial late gadolinium enhancement. This is another study where we did a quantitative approach in terms of measuring the pericardial LGE, but I would just highlight that red curve at the bottom. That highest fourth quartile are the most severe cases. Those are patients who, again, over a treatment period of some years are very unlikely to develop clinical improvement or remission. Again, I think there's still a lot to learn in understanding these patients, but clearly the ones who have high CRP and very abnormal MRIs are higher risk and need a long duration of treatment.

(00:44:53):

He was started on an interleukin-1 blocker, and then after two weeks, we were able to relatively rapidly taper off the prednisone, which again, I think is something we have learned in the interleukin-1 blocker era is that we can taper the corticosteroids more quickly. We all have different practice patterns, but I usually like to get the patient off the steroids first, and then see if we can wean the colchicine, which we were able to do in this patient after an additional two weeks.

(00:45:20):

And then, again, as I mentioned at the outset, I mean, this was a guy who was very into fitness. He had jobs related to physical fitness, and really wanted to return to exercise. And after no recurrence for 12 months, I did allow him to return to gradual increase in physical activity, and is currently now able to run several miles a few times a week. Again, I think this is a place that's evolving and an area of controversy, but I think something that's very important for the quality of life of our patients.

(00:45:57):

And this is just a slide really to emphasize that we don't really know a lot in terms of the pathobiology in terms of why exercise exacerbates pericarditis, but we certainly see it clinically. Maybe it's related to oxidative stress, just increased heart rate, and I think there's a story there to be told, as well, in terms of the heart rate control. But I think this is really an area that's unknown and should be investigated further.

(00:46:27):

Maybe I'll stop there and ask Allan or Brittany, any comments on the case and in terms of your thoughts?

Brittany Weber (00:46:36):

Yeah.

Allan Klein (00:46:36):

The exercise piece, as I mentioned, is a big story because this particular person has a bad case and you're telling him, "Exercise is not such the best thing, and according to guidelines." And you're responding to the biologic. When can you back to exercise?

Brittany Weber (00:46:56):

Exactly.

Allan Klein (00:46:58):

Everybody's a little bit different. The ones that I've said returned to exercise, often they call you Monday morning, and they have a recurrence. I said, "What you do?" "Well, I biked 40 miles." I says, "Why'd you do that?"

(00:47:09):

Or I've had an Olympian, actually a public knowledge Olympian in basketball, who's a coach for University of South Carolina. She disregarded my advice. She's an Olympian. You got to do your workouts. She flared, and you see the MRI got worse, and then gradually calmed it down, but we don't really know. On the other hand, we don't want to take away their spirits. They're already living with a chronic problem, moving, so it's hard to tell them. But-

Brittany Weber (00:47:40):

[inaudible 00:47:41].

Allan Klein (00:47:41):

... Paul and then Brittany, how do you handle exercise?

Brittany Weber (00:47:43):

Now, I agree and I think this is such an important question for future research. It's not even a joke that it's always the patients that are really... It's a important part of their life, and we're essentially telling them they can't exercise.

(00:47:56):

And now, we have this amazing treatment that really can decrease their symptoms and take aware their flares. And you just saw the RHAPSODY long-term extension data that says greater than 18 months, so we're talking about years, or potentially lifelong therapy for these patients. Does that mean they can never go back? And then how do we think about the timing and the gradual versus increase? So this really an important question for the future for us to study, especially with these new agents.

Paul Cremer (00:48:21):

Yeah, that's a great point. I think we all have different practice patterns, so I'll just say my own practice, which is no one else's, and so take it for what it's worth, is you usually have a heart rate target that the patient's been restricted to, and I have said, "You can increase it by five beats per minute per month." That forces a gradual reintroduction of exercise.

(00:48:42):

And they're also quite deconditioned because they haven't been exercising for like a year. So you don't want them, in that sense, to go do 40 miles and get injured. But that's something I just made up, but that's what I use in my clinical practice, and it does seem to work in the limited patients where we've been able to do this with our current therapies.

Allan Klein (00:48:59):

So we're about to do a study with the digital watch, WHOOP device, where we're going to randomize roughly, in a pilot fashion, 10 patients with active exercise. They can do what they want. We'll be tracking their heart rates-

Paul Cremer (00:49:16):

[inaudible 00:49:16].

Brittany Weber (00:49:16):

[inaudible 00:49:16].

Allan Klein (00:49:16):

... and their Strive Scores, their sleep patterns, and the other 10 will limit their exercise and see who's going to flare first. They'll be inflamed equally and with the exercise. And then there's a lot of talk for doing some prospective work with exercise. But that's the biggest fight in the office. Some people say, "I don't want to even be on the drug. Let me do a pericardiectomy so I can go back to the gym." So this is a big major issue in the [inaudible 00:49:48].

(00:49:48):

My other question is about the first cases after open heart, right?

Brittany Weber (00:49:52):

Yeah.

Paul Cremer (00:49:53):

Right.

Allan Klein (00:49:53):

Do you see a difference in the story with a viral presentation versus the open heart story?

Paul Cremer (00:50:00):

Right. I think we've talked about this. When we have the multiple recurrent patient, that's an auto-inflammatory phenotype, which is a lot of them, or most of the patients in our clinic. I can't really tell the difference, clinically. And sometimes I have to remind myself, was this, initially, an idiopathic patient, or did they have mitral valve repair five years ago?

(00:50:24):

It's one thing, what's the risk of recurrence after the acute event? I think that's very different dependent on which is it? Are we talking about ablation, or a pacemaker, or aortic surgery versus other things? But once you develop multiple recurrences, I think the treatment approach, at least for me, is essentially identical.

Allan Klein (00:50:40):

Okay.

Paul Cremer (00:50:44):

Excellent. So I'll, yeah, transition to the next case. I think this is a little bit more of a controversial case, if you will. This is a 71-year-old gentleman who had acute pericarditis after a presumed viral infection. The workup was otherwise unremarkable. There was an initial delay to diagnosis. He was started on colchicine after a few weeks. He continued to have chest pain and noted some lower extremity edema. And after a couple of months of really struggling through this, we started on prednisone at 40 mg daily.

Audience (00:51:17):

Wow.

Paul Cremer (00:51:17):

And when he came to see me in clinic, so we're now 3.5 months, three and a half months into his symptoms, so this is a patient with chronic pericarditis, he's still having chest pain. He's got evidence of right heart failure with jugular venous distention, abdominal fullness, and lower extremity edema. His CRP is 10.4 mg per liter. But again, this is on 40 mg of prednisone.

(00:51:45):

And this is his echocardiogram. In the parasternal long-axis view, what you can see is a respirophasic septal shift. And there's so many features of constrictive pericarditis, it's good to have, in my view, what... When I talk to the Fellows, what are the things we really want to focus on? Well, it really starts with seeing that respirophasic septal shift. That's the hallmark of constriction, which you can see here on the parasternal long-axis and short-axis views. You usually see it best on the short axis at a basal or a mid-ventricular slice. And here's looking at his mitral inflow. There's really a steep deceleration to the E-wave, that sort of rapid diastolic filling, and then cessation that you can see in constriction.

(00:52:33):

And then the other important feature I think that to emphasize is looking at your tissue doppler, and specifically looking at the septal E-prime velocity, and that being elevated or accentuated. We talk about annulus reversus, which is where that septal E-prime is higher than the lateral E-prime tissue doppler velocity, which is the inverse of the normal condition. So respirophasic septal shift, I look closely at the pulsed-wave and tissue doppler.

(00:53:01):

Here's one of the newer features that was highlighted where we can often see that the global longitudinal strain is overall preserved, but there can be some regional decrease here, in the lateral wall, as it's being tethered by the thickened pericardium. But then I think after the respirophasic shift and your tissue doppler assessment, looking at the IVC. Here, the IVC is plethoric without respirophasic variation. It is very difficult to have constriction with an IVC that's not dilated.

(00:53:33):

And then the other feature that's quite helpful, but is the most difficult, I would say, to reproduce, is looking in the hepatic vein profile. What we look for is a prominent expiratory flow reversal in the hepatic veins. So everything that shifts one way, during inspiration, shifts the other way, during expiration.

(00:53:52):

So I think this patient is coming in with constrictive pericarditis. And I think, as Allan touched upon, the spectrum of pericarditis, when I see a patient, there's two things questions I ask is, one, how bad is that inflammation? And what are the hemodynamic consequences?

(00:54:08):

Here, we have a patient who has a lot of inflammation and also has a constrictive pathophysiology. Whereas conversely, you can have a patient who's burnt out, who's got a calcified pericardium. There's no inflammation, but has constriction, as well. So I think it's really important to make that distinction.

(00:54:27):

And this is, it worked that Allan mentored me on some years back now, when I was a Fellow, looking at-

Allan Klein (00:54:33):

When you were a kid.

Paul Cremer (00:54:34):

When I was a kid, yeah.

Allan Klein (00:54:35):

When he was just a little kid.

Paul Cremer (00:54:37):

Now, I'm all grown up. But basically, the idea was to look at patients who have constriction, who went for MRI. And does the pericardial late gadolinium enhancement help us? We use that to say that if there's a lot of late gadolinium enhancement, there's active inflammation, those patients should try medical therapy before going straight to pericardiectomy. And I would emphasize that this is before the interleukin-1 blocker era. And even then, you could resolve a lot of these cases without needing to go to surgery.

(00:55:08):

He was diagnosed with active inflammation and constrictive pathophysiology. He was symptomatic with chest pain and elevated inflammatory markers on corticosteroids. So this is a patient that I transitioned to rilonacept, and I'm actually going to see him, I don't know if it's next week or the week after, to see how he's responded.

(00:55:27):

But I would say, one, I think we can resolve constriction in a lot of these patients, at least that's my hypothesis. And I would say, even if we don't, you want to treat this inflammation very aggressively before sending a patient with a lot of inflammation to pericardiectomy. That's been our clinical experience is, even if you're not able to resolve the constriction, you need to aggressively treat that to have a safe and really the best result after surgery. So I think there's two really good reasons to consider an interleukin-1 blocker in this type of patient, who is a chronic pericarditis with a lot of inflammation, who had developed a constrictive pericarditis.

Allan Klein (00:56:11):

So very good. Now, let me just to add a comment. That's an important message. Don't send your patients for pericardiectomy if they're inflamed. Actually, we did have a case like that. The message, well, it didn't get to the surgeon. The surgeon tried to operate. It was basically a surgical minefield. By accident, he cut the LAD and had to close him up. It was a real mess.

(00:56:37):

So basically, treat the inflammation three to six months plus, get the inflammation down, and then you have to decide whether symptoms are better, or do you keep on persisting, or now is the time for pericardiectomy. Calm it down, and IL-1 blockers may be the way to go with this.

(00:56:55):

Brittany, so you're up.

Brittany Weber (00:56:56):

Yeah. Thank you very much, Allan, and Imazio, who had to leave, and Paul, for the opportunity to be here to talk to you about these very challenging but exciting era for us. This case number three is a little bit quicker and it's also a more complicated, nuanced case. It's to highlight, though, some of the important questions that we all struggle with in our challenging patient population, and also how we think forward, moving the other areas of where IL-1 blockade could be used.

(00:57:24):

This is a 60-year-old male who presented to the emergency room with severe chest pain, fatigue, shortness of breath. He had a lot of facial swelling, nausea and vomiting. It was one week after his COVID vaccine. And we've all heard the frequency of COVID vaccine and also COVID, itself, causing different myocarditis or pericarditis.

(00:57:48):

You'll see his past medical history here. He has hypertension, moderate to severe psoriasis. That is relevant because he actually came in, presented to us, and he was taking an IL-23 inhibitor, which is a common anti-inflammatory biologic that's utilized for at least moderate or severe disease. He was very well controlled on that. He's also on testosterone replacement therapy.

(00:58:09):

And here's his initial episode. You can see his hemodynamics. He was stable. You could see he had emergency room labs, as shown here, which pretty unremarkable EKG and echo, at that time, and pretty low inflammatory markers on our assay. So this is before I was involved in his care, but this is how it was in the emergency room, is that he was actually given a low dose of prednisone for a presumed allergic reaction after a brief ED Op stay. However, he went home with continued symptoms after he was on those very short steroid course.

(00:58:48):

So basically, his primary care physician restarted the steroids and also started some diuretics for some lower extremity swelling because I told you he had that history of heart failure with preserved ejection fraction. At that point, he was referred to see an out-patient cardiologist, but he came back to the emergency room with progressive symptoms. As oftentimes, these patients, they go to the ED because they don't know where else to go with their worsening symptoms.

(00:59:11):

At that workup, he was, again, afebrile with stable vital signs, but you can see his labs were was significantly different. He now had an EKG with prominent ST elevations and positive cardiac biomarkers, including a high sensitive of troponin shown here of 559, high sensitivity as well as an ultra, a high sensitive CRP of 207 mg per liter, so very different, elevated ESR, as well. At that point, a cardiac MRI was obtained.

(00:59:41):

I'm showing you the prominent features here. On the left, the red arrow is pointing to what is a mid to apical lateral wall focal transmural LGE in the myocardium. He also, though, had significant LGE of the pericardium, as well as a small pericardial effusion shown on the two pictures on the right. So this was a diagnosis of myopericarditis. You probably see the terms perimyocarditis or myopericarditis. It's often the which way you put those terms is what is the most prominent feature on the imaging. This patient had a lot of more pericardial inflammation in relation to the focal myocardial inflammation.

(01:00:23):

So at this point, his chest pain had improved in the hospital. The prednisone that was started as an outpatient was stopped, and he was finally put on indomethacin and colchicine, at this point. And then went home on these therapies with a very slow taper of the NSAIDs as well as persistent colchicine. However, he then had recurrent chest pain seven weeks here, and he came back to the emergency room with recurrence of these symptoms. Again, I'm showing you his workup here where he then had an EKG that looked, had resolution of his ST elevations from that first hospitalization, but his cardiac biomarkers, although his troponin was now down, his CRP and ESR were persistently elevated.

(01:01:07):

At that point, an echo was performed. I'm showing you just one representative video here. Paul walked you through very nice features of constrictive physiology on a echo, and this video is really showing you a clear evidence of tamponade physiology where you see not only a large pericardial effusion, but what you can see here in that video, and is what shown here on the still images is, is diastolic collapse of the RV, which was one of our echocardiographic signal features of echocardiograph as a tamponade, but as we all know, this is a clinical diagnosis as well. But he certainly had tamponade physiology. Here, I'm just showing you his respiratory variation, the mitral valve starting here, that he had significant respiratory variation in the mitral E-wave velocity shown here.

(01:01:56):

This is a more challenging case without clear guideline evidence, but I'm curious to... There's not going to be one right answer here, but which of the following is the next best step in the management of really what is incessant myopericarditis for this patient? Would you continue his endomethacin and colchicine and just provide reassurance that this is going to improve, restart steroids, or consider starting an IL-1 inhibitor in addition to continuing the colchicine, or perform a biopsy, in this case? And we'll allow the poll to take.

Allan Klein (01:02:25):

So Brittany, that's a tough question.

Brittany Weber (01:02:29):

Yes.

Allan Klein (01:02:29):

It's a tough case.

Paul Cremer (01:02:30):

Yeah.

Brittany Weber (01:02:30):

[inaudible 01:02:31].

Paul Cremer (01:02:30):

And I would say, as these cases have progressed, we've gotten, what I feel as cardiologists, make us more and more uncomfortable where we're outside of where there's really clear, evidence-based guidelines. But, yeah, I think it's a fantastic and complicated clinical scenario.

(01:02:58):

Wonderful. You've learned well. I think we're [inaudible 01:03:02] from this talk. Again, performing a car-myo biopsy is interesting because he did have that evidence of myocarditis. But the most prominent feature was the pericarditis. And that second episode was really just pericardial inflammation by the biomarkers with negative troponins.

(01:03:22):

So this is actually what we did. We actually started him on anakinra. He underwent an urgent pericardiocentesis because of that tamponade physiology. He had 580 ccs of serosanguineous fluid drained that went to gram stain cultures, microscopy, all of which were unrevealing, which is an important feature. And then he was started on anakinra.

(01:03:46):

Anakinra is what needs to be started in hospital. We're not able, at this time, to get rilonacept as an inpatient, so he was started on anakinra, rapidly felt better, and treatment continued. Of an anecdote, just to show you just the nuances of these, is that the patient, himself, who had improved quite rapidly, really was persistent on wanting to come off therapy, a bodybuilder. And when he tried to, he had another flare and was readmitted. You saw data earlier on the RHAPSODY long-term extension. So he is back on therapy, doing well, and hoping not to taper for a while on him, as we see in these complicated cases.

(01:04:26):

So unless Allan, well, thinks we should stop, I'll just move... Oh. Oh, so I'm going to conclude with these cases. A few teaching points here is that COVID-19 infection and COVID-19 vaccine-induced myopericarditis is very uncommon. This is a very uncommon scenario I'm presenting here. I should just point out, these cases are published on our acc.org pericardial disease collection, which is a fantastic learning content. So this is actually a published case, if anybody's curious to hear more about the case. Isolated myocarditis or pericarditis, without both together, can also occur.

(01:05:00):

Most cases, though, are self-limited. This is also what the data supports. They resolve with standard treatment, but you can see here that there can be certainly indications of more complicated cases. For incessant refractory cases, the best [inaudible 01:05:12] approach is not as unknown. This has not been studied, but this example highlights how this patient had successful stabilization with IL-1 inhibition started as an inpatient, but when and how to taper the therapy is a big unknown question.

Paul Cremer (01:05:29):

Yeah, it's a great case. I mean, I would just add also the question that comes up a lot is, "I'm on an interleukin-1 blocker. I'm going to get the vaccine. Should I stop it? Should I stop my interleukin-1 blocker?" The answer to that is no.

Brittany Weber (01:05:44):

Okay.

Paul Cremer (01:05:45):

Just to emphasize that point, which I think we saw in the abstract today from RHAPSODY. And also the American College of Rheumatology is clear that these therapies should be continued through vaccination.

 

Brittany Weber (01:06:07):

This is right. Exactly. And it's an important message for patients because they're often quite scared. This is a lot of the phone calls we get. The rheumatologists have clear guidelines on this. I utilize my rheumatology colleagues for a lot of these questions because there are certain drugs that they may withhold, but this is not one of them.

Allan Klein (01:06:21):

Right. In terms of your practice, how many calls are you getting about the vaccine-

Brittany Weber (01:06:29):

A lot.

Allan Klein (01:06:29):

... and myopericarditis, or, you know.

Brittany Weber (01:06:31):

Yeah.

Allan Klein (01:06:33):

Or you're seeing the outpatient. He had the vaccine or the booster, and they have chest pain. Is that common? No?

Brittany Weber (01:06:39):

It's not uncommon. And I'm curious to hear if anybody in the audience, a fear of getting it, and then also presenting with symptoms. And then that's where you do the diagnostic workup to see if there's indication of that.

Allan Klein (01:06:54):

And Paul, the role of MRI, and this is a good MRI as opposed to a vague MRI, but that's an issue. Right?

Paul Cremer (01:07:04):

Yeah, and I think it's essential. I'd say, clearly, the focus here is on pericarditis. He showed an amazing case of perimyocarditis. But remember, when these patients come to you with chest pain, there's a differential. So I've had patients who get the vaccine, "I got chest pain." Of course, you want to exclude an acute coronary syndrome, but you diagnose Afib, and the patient probably had a cardioembolic event. So I think the cardiac MRI is not only helpful for delineating the severity of the pericarditis, but also can tell you about, if you see subendocardial-

Brittany Weber (01:07:38):

Exactly.

Paul Cremer (01:07:39):

... late gadolinium enhancement, I'm thinking about ischemic idiologies, as well.

Brittany Weber (01:07:41):

Right. And it can rule out the absence of it, right?

Paul Cremer (01:07:41):

Yeah.

Brittany Weber (01:07:41):

I had a referral from primary care that had two ED admissions for this chest pain, but no clear objective data. And it was not clear if there was pericarditis or myocarditis, and so was finally referred. And I order a cardiac MRI and I show the absence of either. Actually, it's important data to be able to inform the patient.

Allan Klein (01:08:06):

Yeah. Yeah, in my practice, at Cleveland, I would say 20% plus get referred to this tertiary care center, and they don't have pericarditis. 20%.

(01:08:26):

And objectively, getting back to the criteria, you look at each thing, and you look for some evidence, and you could say, "It's two possibilities, either it got better dramatically, or you never really had it." It's good news for them because now you can start taking them off all this, and, "You can go to the gym, and you can wean slowly." But that's an issue in the practice now.

(01:08:51):

But okay, so Brittany, so let's-

Brittany Weber (01:08:52):

Yeah.

Allan Klein (01:08:52):

... see how you use a IL-1 blockers.

 

Brittany Weber:

 First, just really hitting home key learning points from these talks today is remembering how do we identify recurrent pericarditis. You saw Allan show you the guidelines, remembering that we utilize our ESC guidelines. And just the definition of what recurrent pericarditis is, is that the definition really is, is a recurrence after you have been symptom free of an acute episode. Although we discussed, tonight, challenging cases of incessant, where they may not have that four to six period free week.

(01:09:39):

But also, in addition to the actual definition of the time is actually really understanding the quality of the chest pain and really recognizing that patients with recurrent pericarditis may not have these classic features we see in acute. That's where we really need to look for other objective evidence to support our diagnosis. This is where we've talked a lot about imaging.

(01:09:59):

You also heard and Allan's talked earlier is how do we assess the risk in somebody that could have recurrent pericarditis? We can think about it about treatment related, patient related, and ones that are not related. Treatment-related variables associated with increased risk, you saw data tonight on this of corticosteroid use, especially rapid dosing or high-dose dosing early on. The lack of colchicine, we didn't present that data tonight, but that's well known. Also work now that if they don't get colchicine, they're more likely.

(01:10:30):

Patient-related variables with increased risk, incomplete response to non-steroid anti-inflammatory drugs, as well as an elevated, high-sensitive CRP, which you saw in Paul's talk tonight. And then patient-related variables without increased risk that we all may wonder about is whether somebody presents with a pericardial effusion, does that mean they're going to be set up for recurrent pericarditis? And the answer is no, from our data, are also gender specific, or also in age, although we did see a little bit tonight.

(01:11:03):

But then it really is us, as clinicians, taking a good medical history. These really, they take time. There's a really teasing out what can be complicated and also not clear from the charts, especially when patients often present to primary care, emergency rooms, and you're trying to tease out the data. So it's taking a very good patient history, thinking about what are their risk factors? What could have predisposed those episodes? Do you have any imaging? Could you utilize multimodality imaging in this? And thinking through the pathophysiology.

(01:11:32):

And as a cardio-rheumatologist, I think a lot about the immune system. I like to think of it in two broad cascades. You heard a lot tonight about how recurrent pericarditis is really an auto-inflammatory disease. We also talked about that many cases... not many, but a subset of cases can be triggered by autoimmunity.

(01:11:50):

So what is the difference in these? There is some key differences in this. They both cause chronic activation of the immune system. And although the autoimmune diseases have an innate immune component, it's often the initiating feature. They have adaptive immune system. What I mean with adaptive immunity? That's really what we're talking about specificity, so B cells and T cells. And not only is that the cytokine be a little different, the treatment patterns can be different in these. But ultimately for the patient, it's really leading down to tissue inflammation and damage. So these patients are presenting to us, but their pathophysiology may be different, and their treatments may be different.

(01:12:27):

And this is just a diagram showing you that autoimmune diseases in cardio-rheumatology can be complex. There are a lot of different rheumatologic diseases that the rheumatologists take care of that have pericarditis as features of their disease. I've put into buckets here, the connective tissue diseases, the vasculities, the more rare infiltrated diseases shown here on the bottom, as well as auto-inflammatory. We heard a lot about the mono-genetic as well as more poly-genetic disorders in the auto-inflammatory on the left, which seem to respond very well to this inflammasome IL-1 inhibition.

(01:13:03):

But you can see in the bucket in the middle, with the font-size, is shown as lupus. As Allan mentioned in a case earlier, I will say the most common disease I treat, and they can be very refractory over the lifetime, is patients with lupus pericarditis. You can still see it within these other subsets in them, the vasculities, although a less common disease overall, ETPA, eosinophilic granulomatosis polyangiitis, I know that's a hard word to say, but that would be the most common vasculity that can present with pericarditis.

(01:13:35):

So going back to really utilizing the role of imaging, especially when we're going to be applying these IL-1 biologics we're about to. You've seen a lot of data tonight about these therapies are really going to be need to be longer term, so really having objective data for us to start with and monitor over time.

(01:13:53):

And you've seen a lot on this, but this is really just to hammer home that there's really excellent clinical guidance, within JACC and CIRCIMAGING, of really guide us in how we can use cardiac MRI. You get both the morphology, the pericardium, the effusion and thickening. You can look for inflammation with cardiac MRI, which you cannot see on echocardiogram. Could also quantify ventricular size and function, and then you can look at the physiologic effects of constriction. This is why you've heard us a lot, tonight, talking about the role of cardiac MRI.

(01:14:22):

And this is just, again, highlighting a wonderful paper here, from Allan's, in CIRC, cardiovascular imaging recently, with just the key sequences that we utilize, that we look for, both the black blood spin sequence where we look at pericardial thickening, T2 sequence where we look at pericardial edema, often from inflammation, and then, well, at as well as the late gadolinium enhancement. This is showing severe circumferential enhancement here.

(01:14:49):

I'm going to very be briefly here. This is just a real life [inaudible 01:14:53] really bringing this back to the clinics, is of a patient where I really showing you how I utilized MRI with initiation of IL-1 blockade. So it's a patient with idiopathic recurrent pericarditis, not showing you the clinical features here, but just showing you the MRI, which shows us all the key features of recurrent pericarditis, increased pericardial thickness, pericardial enhancement, pericardial edema, no constrictive physiology.

(01:15:19):

This patient was put on rilonacept after NSAIDs and colchicine, so failed it after two episodes. Did not get steroids, which we talked about how this can be... utilize this approach now. So she continued rilonacept with colchacine, as you heard from Imazio. She had no recurrent flares when she started on this therapy. There was a cardiac MRI that was repeated at five months that was showing mild improvement, but the MRI can take a long time to show changes. But really by a year and a half, it actually has almost completely resolved.

(01:15:51):

This is showing you her follow-up MRI at 15 months here, where we actually don't see any late gadolinium enhancement, and we see resolution of the pericardial effusion and normal pericardial thickness. So she's now been stable since. This is really highlighting how we can utilize imaging when we're applying these IL-1 blockades to our patients.

(01:16:10):

You saw this slide earlier in Allan's talk. This is just going hammering home the European guidelines that we use, but really hoping not only advocating for the need for ACC and AHA guidelines, but also showing you here that this second line, that once you've failed aspirin or NSAIDs and colchicine, that you could really be IL-1 receptor, off this, could obviate the second-line need for corticosteroids.

(01:16:39):

Practical considerations for starting a biologic, I know it's a newer drug for a lot of cardiologists to be starting patients on these drugs, but it's often just getting familiar with how to do them and what you monitor. So prior to starting, this is what I would do in my clinic, and I learned from the rheumatologists on my practice patterns, but I get baseline laboratory testing, including CVCs and LFTs, check hepatitis B and C serologies on every patient, as well as TB testing. Everyone needs a TB test. Oftentimes, that's required, often, to get the drug approved.

(01:17:17):

Assessing vaccination status and also having discussion with the patient of making sure that they're up to date and recommending based on age appropriate what they'd be appropriate for, and then assessing for potential contraindications. As we see with our challenging patients, this is important. Active infection, these cannot be utilized in pregnancy, which is another unique population that would require different treatment, and then, of course, of active malignancy. During treatment, regulatory monitoring for the safety and efficacy of their drug response, and then we're always checking routine labs every couple of months.

(01:17:51):

We've talked a lot tonight about biologic therapy discontinuation. This is why. You can see here we don't have a lot of guidance yet because we're still learning. This RHAPSODY long-term extension just came out today, and we are really learning that they probably need much longer therapy. So it's really individualizing the appropriateness of discontinuation and deciding on a weaning plan, whether if that's on anakindra, you may be weaning anakindra versus stopping rilonacept. So if you are going to stop, establishing a plan for the patient and as well as how you're going to monitor for disease recurrence.

(01:18:27):

You're not going to see a tapering plan here for the bioligics because we don't have guidance on how we would wean or stop these, but you can see here there is clear guidance on how you would stop the standard first and second-line treatments. This is just a well-known reference that anybody can utilize. But a suggestive pattern for cardiologists, they can use when they're tapering the NSAIDs. Colchicine, although some of us may still, and I do at times taper colchicine, it's really not necessary. But really highlighting that prednisone requires low doses, but very slow and long taper.

(01:19:01):

So some tips for tapering, taper one class of drug at a time, especially when the symptoms have resolved and the CRP levels are normal. You really need to go very slow with these patients. Taper slowly. Tell the patient this is going to take several months. Be conservative with your steroids and really reserve them for when they're refractory, and then just clear communication with your patients that they could clearly have a recurrence, that this is going to be a lifelong disease here.

(01:19:28):

And I'm just going to end with one slide here is that these are complicated patients, as you heard tonight. It really is a role for multidisciplinary team care for recurrent pericarditis. This is the patient in the middle, but this is the multiple things that get involved in these patients' care. Not only is that the central as us, as cardiologists, but often we need support. That support includes our RNs and our PAs and MPs. There's a clear role for primary care here, also. I mean, these patients are often going straight first to their primary care.

(01:19:58):

And then all the specialties. You've heard a lot about rheumatology, genetics with the auto-inflammatory, infectious disease oncology, and particularly in the cases that are more malignant. So this really is a multidisciplinary team care and hopefully this can continue to grow across centers. I want to thank you for your time.

 

Allan Klein (01:20:21):

In conclusion, we heard about the diagnosis with MRI, echo, and now we have the biologics. This shows actually very complex, that it's rare to see a very straightforward patient.

 

We have to use the ESC guidelines. It's time for ACC, AHA guidelines. And if you use the guidelines, look at it very objectively. Don't assume. Every resident or Fellow I work with, they come out of the room and they say, "Well, it's obvious pericarditis." Then you take a good history. It's the 20% that don't have it, so you have to be very, very careful. We have to recognize about the pathophysiology of IL-1 as an auto-inflammatory cycle of recurrent pericarditis. We should adopt the IL-1 blockers earlier in the system.

 

Allan Klein (01:29:42):

So very exciting topic. As I said, this is a new renaissance in the field. I want to thank the panel, Paul, Brittany, Dr. Imazio, the audience for coming. And thank you for the support and hopefully this field grows. Thank you very much.

Brittany Weber (01:30:00):

Thank you.