Talking Tall Rounds®: Pericardial Diseases - A New Renaissance in Imaging and Treatment

Podcast Transcript

Announcer:
Welcome to the Talking Tall Rounds Series, brought to you by the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic.

Eric Roselli, MD:
Hello, everyone. Welcome to another Talking Tall Rounds® Podcast from the Cleveland Clinic, Heart Vascular & Thoracic Institute. I'm Eric Roselli, and I'm here with my good friend and colleague Doug Johnston, we've worked together since 2000 and... I don't know, when did you get here, Doug? Was it-

Douglas Johnston, MD:
2005.

Eric Roselli, MD:
2005. Yeah. That's a long time, man.

Douglas Johnston, MD:
It's a long time.

Eric Roselli, MD:
So it's been a lot of fun, right? So Doug Johnston is the Program Director of our Training Program, he's the Vice Chairman in the Department of Thoracic and Cardiovascular Surgery, and a world renowned surgeon with a lot of actual areas of particular interest, but one of his particular interests as the Surgical Director of the Pericardial Center is treating complex pericardial disease. And we're here today to discuss the Tall Round® session that we did on that topic called Pericardial Diseases: a New Renaissance in Imaging and Treatment. Thanks for joining me, Doug.

Douglas Johnston, MD:
It's great to be here, thanks Eric.

Eric Roselli, MD:
So this session, no surprise of course, was led off by Allan Klein, who is another really well-known cardiologists in our group, he was the President of the Society of Echocardiography, and is also known really well for all the work that he's done on pericardial disease. A very nice overview of the program. You’ve worked pretty closely with Allan for quite some time, didn't you Doug?

Douglas Johnston, MD:
Yeah. Allan is obviously illuminary in the world of pericardial disease, he's incredibly passionate about it and he's done a lot to drive, not only the research, but the systematic thinking about how to treat these patients medically, especially the inflammatory pericarditis population, and also for a cardiologist who's very focused on imaging, has been very bullish about the possibility of surgery early in the course of disease being a game-changer for these patients who are often steroid-dependent. So, Allan's really a forceful personality, obviously, in this area and a great advocate for patients, but he's been a great partner to work with over the years as I've transitioned into this practice that really was pioneered here by Bruce Lytle. Allan's been the bellwether for all of the developments in the field and just super passionate about it.

Eric Roselli, MD:
Yeah, it's pretty awesome, there's a lot of rare things that come through here in much more sort of commonly in our large center, and having someone take the lead from a medical perspective to work alongside the surgical team, and really have a multidisciplinary approach to these patients has allowed us to really make some progress in a relatively short period of time.

Eric Roselli, MD:
The case that was presented, which is... Again, along with our typical format for these Tall Rounds® was presented by Michael Chetrit, one of our fellows who did a really nice job, and I thought it was cool that in keeping with the variable presentations of pericardial disease, he presented two different cases, the one was a patient who had a post- or who was post-SVT ablation, and also I think had some PCI or something and initially responded to some steroids, and then the other one was a patient had the viral syndrome. So both quite unusual problems, but can really be devastating for patients, and that patient developed hepatic congestion and calcification, and ended up going to the OR with you. You see a pretty broad spectrum of patients who present with this, don't you?

Douglas Johnston, MD:
Yeah. We're fortunate in the Pericardial Center to have a bunch of cardiologists who are very interested in all the phases. I think the thing that is most interesting to me is that people tend to focus on the two ends of the spectrum of this disease, people focus on the typical presentation of acute pericarditis, which is most often fairly benign, it's self-limited and often is treated with colchicine or even ibuprofen, sometimes a short course of steroids, and it's assumed that those patients are fully treated and will never need to be seen again. And then there's a lot of focus on the end-stage constriction patients who are perceived as this very high risk surgical population that is really at the end of a devastating disease process.

Douglas Johnston, MD:
There's been relatively little focus on the in-between, which is the vast majority of patients, which are people who have maybe had an episode of pericarditis, and then have some kind of recurrent syndrome from mild to severe. Those are patients who really benefit from a focused medical approach where steroids are not the only drug that's available now, fortunately, and we have this spectrum of newer anti-inflammatories, including rilonacept, which can really make a difference in many of these patients. But it takes a thoughtful cardiology team to decide, when is enough therapy? And what we've learned over the years is you can't just shotgun this, you can't just give somebody three weeks or a month and cut them off cold turkey, and hope that that's going to do it, because if they are treatable with medication, many of these patients will take six to eight months to get better, and the ones that are successfully treated need to be weaned incredibly slowly off their meds.

Douglas Johnston, MD:
So we see patients who have been treated successfully cold turkey, those who have been treated successfully, they cut off, they relapse, and that's a difficult population. And then the other end is these patients with constriction who maybe for years have mild symptoms of fatigue, and then all of a sudden they get ankle swelling and often they're misdiagnosed. So it's very satisfying to get somebody to a diagnosis and say, "Hey, okay, at least we know what this disease is, and now we can think about what, and when is the right time to treat you."

Eric Roselli, MD:
I think that's a really important insight because the patients who get lost in that phase in between, depending on how stoic a patient is, or their own... I don't know, denial of symptoms, they can really struggle for quite some time in that intermediate phase of disease and they get lost, and yet we have lots of options to help those people.

Douglas Johnston, MD:
Yeah. And otherwise healthy people... I think much like valve disease, if you're otherwise healthy, and you got pericardial constriction, you can tolerate it for a long time. And sometimes these people get to the point where they have cardiac cirrhosis, and they have real metabolic derangement because of their constriction, and really only in the couple of months before presentation have they really felt badly. So it's very subtle and slow, and as I said, often misdiagnosed. So it really behooves those taking care of these patients to think about pericardial disease early, and if there's suspicion for it, there's lots of guidance that a place like this can provide, you don't always have to send the patient to the Cleveland Clinic, but I mean, we're always available to say, "What kind of imaging should we get?" And then once we have a diagnosis, we can be a lot more thoughtful, but getting to that point is the key.

Eric Roselli, MD:
Yeah. It’s part of the cardiovascular system doesn't get a whole lot of attention, and I thought that was cool for the Tall Rounds® where we started out with hearing from Christine Jellis who is another one of our cardiology imaging specialists, and she focused on the topic of the pathophysiology, and gave this clinical perspective, and a really nice review of the different etiologies post MI, post pericardotomy, post-intervention, described the various phases, acute, incessant, transient, effusive, and chronic, and then talked through the spectrum of inflammatory fibrotic and transient bits of the disease, and I thought that gave a real nice setup, and then right after that, we heard from Rene Rodriguez who has... Gosh, how long has Rene worked here, and in Cardiovascular Pathology? For decades, right?

Douglas Johnston, MD:
Yes.

Eric Roselli, MD:
I mean, he's seen everything, and he showed some really great slides and talked to us, which was cool to hear again, because again, pericardium is for a lot of surgeons, just something you cut through and move out of the way to get to the heart, and I think for a lot of cardiologists, maybe they stick a needle through it once in a while, but... Or like you said, "cool someone off with a brief episode of pericarditis," but really deserves more attention. He schooled us again on the anatomy about the differences between parietal and visceral pericardium, and showed us about the vasculature of the structure.

Douglas Johnston, MD:
Yeah. Rene's is amazing, and his insight into the various presentations of this disease is really phenomenal. We're working on a study with his group and Debbie Kwon, looking at the correlates between imaging and pathology findings to try to differentiate those patients with inflammatory pericarditis who have involvement of other structures, if they have really mediastinitis or whether it's pericarditis, try to figure out who's going to be the best candidate for surgical versus medical therapy, and Rene's insight there is just phenomenal.

Eric Roselli, MD:
That's really cool. Tell me a little more about that case you helped him with the other day where you removed all that... we did that radical pericardiectomy on that guy, which is again, a fascinating case and he's doing fantastic, I can't believe how much he diuresed afterward.

Douglas Johnston, MD:
Yeah.

Eric Roselli, MD:
But it was important that we were marking the specimens for that study. It's a really cool example of how an imaging specialist and a pathologist are working together to discover what's happening. Can you tell us a little more about that?

Douglas Johnston, MD:
Yes. So one of the things that's fascinating about this is how patchy it is, and in what we'll often hear in somebody where they think the diagnosis is equivocal is, "Well, we don't see thickening that's circumferential, or the calcification is only in a couple of areas," and the sense that this textbook-classical-eggshell-type calcification is what constitutes pericardial constriction. We know that's wrong because most people have patchy calcification, what we don't know well is, are there ways we can use the imaging and the areas of inflammation or calcification to predict how bad things are going to be clinically or what the response to the therapy will be?

Douglas Johnston, MD:
And so the idea behind the study is to say, we'll do systematic resection, which is already what we do, we do a radical pericardiectomy, take all the pericardium out, and then we'll keep the specimen intact and mark it for the pathologist so that they can do sections in various areas and correlate that with the pre-op imaging, and in patients where there's a concern for inflammation, we also do epicardial and myocardial biopsy, epicardial fat and myocardium, just to see whether the inflammation is really limited to the pericardium or whether it's affecting the heart itself.

Douglas Johnston, MD:
And so that's the goal with this is that eventually we'll be able to look at an MRI and say, "Yes, you're somebody who's going to get better with surgery, you're somebody who needs medication first, or maybe medication only." And that we'll have a better understanding of that, but just doing the study, we've learned so much about the dogma of this disease, which is to say, we really don't know based on what the imaging looks like, how much better somebody is going to get with surgery, and given the fact that our outcomes have been so good, we've learned to be more aggressive about just operating earlier, and we've been gratified at how much better so many of those patients have gotten, even though their disease might not look as horrible by imaging.

Eric Roselli, MD:
And that's so cool. We talk about the genetics and their correlation with the development or precision medicine, but we can really use complex imaging, especially with dealing bigger structures. I mean, I can see the work that you guys are doing with that helping to develop, supervise machine-learning tools, so you can look at the regionalization of disease across the pericardium and be probably really precise in guiding therapy and understanding how well somebody is going to do, and well, that's just a whole area where we can learn so much more, those first steps with that kind of study and tying the teams together is just really, really... I think, super exciting.

Eric Roselli, MD:
And we have a pretty big volume of patients to feed into that and probably rolling quite a few patients already. Debbie Kwon, of course, another imaging specialist, she has a particular interest in cross-sectional imaging MRI gave us a nice review of the multimodality imaging that we do in the clinical scenarios for these patients. I loved hearing about her research, but she gave us a really nice review of the things we look for, like intraventricular dependence on echocardiography, some of the current and advanced MRI techniques that are used to really differentiate in the severity of disease, and even talked a little bit about Cine CT which I thought was interesting because obviously where there's calcium, you see that better with CT, although I'm not real familiar with us using much of the Cine CT, have you done much of that?

Douglas Johnston, MD:
That's really a new one. I think it stands to be pretty valuable because it can give a lot of the information that MRI gives, and CT as surgeons, I mean, as you well know, Eric, is the best roadmap we can have. It's easiest for us to manipulate ourselves and just planning how to do an operation, especially in some of these patients with prior bypass surgery or other pitfalls that we have to work around. I think the CT is most valuable to us, so if we can get physiologic information from the Cine CT, that's going to be really cool.

Eric Roselli, MD:
I highly recommend to our listeners to come to Tall Rounds online session and watch Debbie's talk, she's got really cool images to share and our talking about it doesn't do it justice. But our speaker after her is Paul Cremer, and Paul talks about some of the new medical therapies, he's done a really great job working with Allan Klein and the whole pericardial team on the rilonacept trial, I thought it was interesting, he started out talking about how recurrent cases are present 15 to 30% of the time. Is that accurate? Boy that sounds high to me, I didn't realize it was even that high.

Douglas Johnston, MD:
Yeah, I think that's one of the things that this systematic look has really taught us, is that there are a fair number of patients that have some degree of recurrence. What we don't know is whether more aggressive therapy in those early recurrences prevents eventual progression to constriction. So that's going to be a longer term goal of assessing the effectiveness of medical therapy, but in the meantime, it's led to an understanding of how many patients are lost, they have their chest pain, it gets treated and they're sent on their way, and there are a lot of people out there who are suffering with recurrent symptoms that aren't severe enough to be debilitating, but they're severe.

Eric Roselli, MD:
We'll include Dr. Cremer's discussion about these medical therapies NS he does a really nice job at differentiating auto inflammatory versus auto-immune etiologies and the different approaches to therapy for that, and so as soon as we're done here, you'll hear from Dr. Cremer. Paul Cremer is one of our Diagnostic and Imaging Cardiology Specialists, also an Intensivist, and he gives a really great discussion about the medical therapies, both current and new treatments, especially with a nice discussion of the Rilonacept Trial.

Eric Roselli, MD:
And one of the things I remember from his talk, which I thought was cool is he gave a little shout out to Dr. Fauci, they published something about Familial Mediterranean Fever in the 1970s and Pericardial Disease. I thought that was timely and fun to hear from, especially, several months ago when this occurred and we were all in the middle of the worst parts of the pandemic. But then of course, the last resort for folks with the cardiovascular disease and cardiac disease and cardiothoracic disease are the surgeons.

Eric Roselli, MD:
And Doug your discussion about how to handle patients with late stage or end-stage disease, I thought was really great, you gave us a nice history from Churchill to Bruce Lytle, our shared mentor, and where things are at now. You discussed the details of the operation, how you've learned how to do it safer and more consistently complete, and I appreciate the help you gave me the other day when you helped me with one of these cases that I had. I certainly felt a lot more confident about it, knowing that you were there with the great experience that you have. And then you talked to us a little bit about the outcomes, and I thought it was really interesting that you've seen that the etiology seems to play a role in that. Can you tell us a little more about that?

Douglas Johnston, MD:
Yeah. I think the toughest thing over the years has been to differentiate people who have isolated pericarditis, and who have concomitant heart disease, myocardial disease, and etiology totally plays into that. I mean, people who have idiopathic pericarditis, we've gotten much better at being accurate about the diagnosis with MRI, combination of MRI, cath and echo. Those people have an excellent response to surgery, and really the traditional thought that the mortality for those patients is like 10 to 15%, I think we've definitely put that ghost to rest. The current mortality for an idiopathic patient is around 1%-

Eric Roselli, MD:
Wow.

Douglas Johnston, MD:
... and their long-term outcomes are really excellent. Patients with prior heart surgery can also do well, but it really is a very heterogeneous population, it depends on what else they've got going on, they have coronary disease and their heart function is moderate, it's less predictable how they're going to do. And the toughest population is the patients with radiation heart disease, probably because their myocardial disease from the radiation is so severe, but those patients really have very difficult recoveries and very unpredictable outcome, and the long-term survival isn't very good, but some of those patients at five years are still going strong, and our challenge is to figure out how to differentiate who we should operate on with some of this more challenging pathology. That's an area of ongoing study and current with the best imaging we have, we do a great job with idiopathic, and we do a poor job with radiation at predicting who we should intervene on.

Eric Roselli, MD:
It's hard to predict who's going to respond really well, I guess, is that that? In that radiation group, I mean, is that-

Douglas Johnston, MD:
Yeah. In that radiation group, hard to predict who will respond, and hard to predict whose cardiac disease is going to progress fast enough that it doesn't matter what we do with the pericardium. That's the challenging piece. They're often multicomponent disease and how much the pericardium contributes is hard to tease out.

Eric Roselli, MD:
One of the things that... The advances that I think you've really helped to champion is in maintaining the safety of doing these without compromising the ability to have a complete radical resection of pericardium with the use of cardiopulmonary bypass. Do you think that that issue of partial versus complete is something to... It should still be discussed or should everybody get a complete resection, and should it always be done with cardiopulmonary bypass? How about a little surgical perspective there?

Douglas Johnston, MD:
Yeah. Well, that's certainly a softball question to me because you know that I am firmly in favor of doing everybody a bypass and going for a radical resection in everybody. I think we've shown very definitively that's safe, we published that data, we have early data that says that patients with a complete resection live longer, that's in the process of being vetted and we'll hopefully get that out soon. But what bypass allows us to do is be much more consistent and avoid unnecessary injury to cardiac structures during the operation. It's still a matter of debate, certainly, I mean the European Guidelines, which are the only ones that are really fully vetted, the surgical section isn't very big, but what's suggested is a just enough approach, take off enough pericardium where it's safe and you don't get into trouble.

Douglas Johnston, MD:
Well, that's very hard to predict in advance, how do we know what's enough unless we... I had a medical student this year who presented at our research day, who looked at the human dynamic differences between partial and complete resection, and unfortunately we can't tell early on. I mean, you've finished an operation and think everything looks good, and the patient still has residual constriction. So I think that debate should be put to rest, but it's definitely not, and the number of centers that do a lot of pericardiectomy is pretty small. So I think the best thing that we can do is to encourage surgeons who aren't as familiar with this disease that bypass is safe and it allows people to do a controlled operation, and that they shouldn't worry about putting somebody on pump or arresting the heart to do a safe resection with the goal of getting everything out.

Eric Roselli, MD:
Just enough is all of it, right?

Douglas Johnston, MD:
Yeah. Just enough is all of it because otherwise we don't know, I mean, it's very clear that doing a phrenic to phrenic operation is not enough, but when do you stop? That's the question, and we do see patients with recurrent disease who come back years after the first operation, that's a real tough problem to treat, it's very insidious, the outcomes aren't as good. So I think doing it right the first time makes ultimate sense.

Eric Roselli, MD:
I really enjoyed talking with you about this topic, it's fascinating, and to our listeners, please follow us online and, watch the entire Tall Rounds®, you'll see the slides, and the images, and the videos from the operating room and get complimentary CME. Again, Doug I really enjoyed talking with you about this. Can you provide a couple of last words about pericardial disease to close the session for us?

Douglas Johnston, MD:
Well, I think, Eric, I really appreciate the opportunity, it's obviously a passion of mine and really great to highlight the group of a bunch of very dedicated cardiologists. I would just say this is a tough disease, it's very heterogeneous, it's tough to diagnose, and don't hesitate to reach out to somebody who sees a lot of it. Often somebody like Allan Klein, or Christine Jellis, or Paul Cremer can give a little guidance on the phone, and we're happy to help with these patients anywhere, anyhow we can. I recently was contacted by a very experienced surgeon overseas who doesn't see a lot of this and we spent a half hour or so talking through how we approach it, that's a great experience for us, so we're happy to help wherever we can.

Eric Roselli, MD:
Awesome. Well said. Thanks again. Bye everyone.

Douglas Johnston, MD:
Thanks everybody.

Paul Cremer, MD:
I'm going to talk for a few minutes about new treatments in pericarditis, but first, just to frame the epidemiology and what we know about recurrences, so it's about, 5% of all patients with chest pain in the emergency room have acute pericarditis. Fortunately, most of those patients, their symptoms resolve. As Christine mentioned, between 15 and 30% of patients go on to have one recurrence, and once you've had a first recurrence, as many as 50% may all go on to have multiple recurrences. And so we know in these early stages, NSAIDs, and particularly colchicine is quite effective, and in terms of new treatments, we're interested in the patients with multiple recurrences or colchicine-resistant steroid-dependent disease. But again, just to take a step back and think about the history of the disease, when was colchicine first used in pericarditis? So the first description was in 1987, these were three patients who were steroid-dependent, recurrent pericarditis treated with colchicine, and all of these patients they're able to wean off the steroids and were subsequently free of recurrence.

Paul Cremer, MD:
And then this started a large literature of observational and randomized controlled studies looking at the use of colchicine in pericarditis. Here's the IRAP Study, which was in acute pericarditis, and what I would highlight is that it included patients both with idiopathic and post-cardiac injury syndrome, so we now think that there's a lot of similarities in terms of the pathophysiology, and in terms of the primary endpoint, now there was a dramatic reduction in risk of recurrent or incessant pericarditis with a number needed to treat of only four patients. Similarly, in recurrent pericarditis, this is the CORP-2 Trial, which also showed a dramatic reduction in recurrence in patients treated with colchicine versus NSAIDs alone with a number needed to treat of five patients.

Paul Cremer, MD:
But I think if you go back and say, "So why did anyone even think of using colchicine in the first place?" Well, what the authors of this letter said is, on the basis of reported efficacy of colchicine and the recurrent polyserositis seen in familial Mediterranean fever. Okay. So there was noted to be some clinical similarities between familial Mediterranean fever, which I'll talk about as a prototypical auto inflammatory disease, and some of the manifestations of pericarditis. So that was the initial insight to even think about using this drug, and a decade even before then, in 1977, Dr. Fauci and colleagues had described that in certain patients with familial Mediterranean fever, they could take colchicine at the onset of attacks and abort them. And so that really brings to one of my major point here, is that I think we should begin to think of recurrent pericarditis as an predominantly auto inflammatory disease. So when we think about immune disease, it's helpful to think about auto immune disease versus auto inflammatory disease.

Paul Cremer, MD:
And auto inflammation is driven by endogenous dangerous signals perpetuated by interleukin-18, interleukin-1 production, which then leads to interleukin-6 production downstream and production of C-reactive protein. Conversely, auto immune diseases primarily involve activation of T and B cells, characterized by a Type 1 interferon signature. And importantly, this has important implications regarding the efficacy of various biologic agents.

Paul Cremer, MD:
So if you think of the spectrum of... And there's a lot of overlap here, but I think this paradigm is helpful, is this disease predominantly auto inflammatory, or predominantly auto-immune? Is it a systemic disease, or is it organ-specific? And we sort of raised the idea that we should think of recurrent pericarditis at this end of the spectrum as an organ-specific auto inflammatory disease. And when we think about auto inflammatory disease, what we're really talking about is activation of the inflammasome, which happens primarily in two steps. So the first is activation of pathogen-associated molecular patterns or damage-associated molecular patterns that then lead to downstream translocation of NF-kappa beta to the nucleus, which leads to production of pro interleukin-1 beta, which eventually when cleaved by Caspace-1 forms IO-1 Beta.

Paul Cremer, MD:
So that's the first step, and often when we think about auto inflammatory disease, we think of it as sterile inflammation. There's often a second signal that can involve things like reactive oxygen species, which lead to activation of the NLRP3 inflammasome, and the NLRP3 inflammasome here is important for conversion. As I mentioned, a pro interleukin-1 beta to interleukin-1 beta. So how do we think about that in terms of our treatment and diseases? Well, as I mentioned, some of the prototypical auto inflammatory diseases, such as familial Mediterranean fever and Cryopyrin-associated periodic syndrome result in constitutive activation of the NLRP3 inflammasome. And so that's been used as models for therapies that may be effective in pericarditis. If we think about the drugs that we have, so prednisone is known to be a potent inhibitor of NF-kappa beta, colchicine, interestingly inhibits formation of these P2X2 and P2X7 pores, also inhibits caspace-1, and inhibits polymerization of the NLRP3 inflammasome, and of course we have interleukin-1 antagonist, including anakinra, canakinumab and rilonacept which inhibit interleukin-1.

Paul Cremer, MD:
I think what's interesting as an aside in the context of coronary disease, if you think of the CANTOS Trial involving canakinumab, which was a positive result, the recent colchicine data both inhibit the inflammasome, but in the negative trial with methotrexate, there was no inhibition in terms of reduction in CRP interleukin-1 beta and interleukin-1 6. So there may be something to innate immunity and auto inflammation more broadly in cardiac disease. So what do we know about the use of interleukin-1 antagonist in recurrent pericarditis? So this is the AIRTRIP Trial. So this was a randomized withdrawal study design, so they took patients that had pretty severe disease with a mean recurrences of 6.8, everyone received anakinra for two months, and then they were randomized either to continue and anakinra or placebo. And you can see that patients that were randomized to placebo had a very high rate of recurrence.

Paul Cremer, MD:
More recently, we've been involved in a international registry of patients with recurrent pericarditis. This is a total of 224 patients, 55 of which are here from the Cleveland Clinic, followed for a median duration of 17 months, and these patients had a history of four prior recurrences, most of the patients had idiopathic, though some patients had post-cardic injury syndrome and autoimmune disease. Now this is observational data, so it has to be interpreted in that context, but what you can see is there's a dramatic reduction in the terms of rate of recurrence, emergency department visits, and hospitalizations before and after the use of anakinra, and importantly, it helps us to get the majority of patients off of corticosteroids.

Paul Cremer, MD:
One of the areas where I think there's still more to learn is, how long do patients need to be treated? And what should we do about tapering the medications? And as Debbie highlighted, the imaging can be very important to inform that decision, but in this initial experience, what you can see is that in the patients who were treated for a longer period of time and actually had tapering of their anakinra for more than three months, once the drug was stopped, these patients were likely to remain disease-free, whereas patients who had shorter durations of treatment or didn't have tapering were more likely to have recurrence.

Paul Cremer, MD:
So I'll conclude by talking about rilonacept, and the results of a recent Phase 2 Clinical Trial that Dr. Klein presented at the recent American Heart Association. So rilonacept is a dimeric fusion protein that binds interleukin-1 alpha and beta, and this is a drug that's already FDA approved for CAPS, which I mentioned, is one of these typical auto inflammatory diseases, and the way this Phase 2 Clinical Trial worked is that we basically took patients who were symptomatic with active inflammation, so they had a positive CRP or a positive MRI, or we took patients who weren't currently active, but were corticosteroid-dependent. So in total, we had 25 patients, we had a run-in period of six weeks and then an optional extension period extending out to six months.

Paul Cremer, MD:
The primary outcome, this is really just an initial safety and efficacy assessment, we're looking at the decrease in pain and CRP and disease activity after the corticosteroid taper. So after the first dose, there was improvements in patients' pain in CRP with a median time to CRP normalization of nine days, and in patients who were corticosteroid-dependent, the majority were able to discontinue corticosteroids and there were no recurrences in that group during follow-up. In addition, there was improvement in quality of life scores, our imaging features such as pericardial effusion and a delayed pericardial hyper-enhancement also improved.

Paul Cremer, MD:
And again, if we looked at the annualized incidence of pericarditis before and after the use of rilonacept, there was a dramatic reduction. So based on the results of that pilot study, there has been breakthrough designation for rilonacept for the treatment of recurrent pericarditis, and as Dr. Klein mentioned, we're currently enrolling in the RHAPSODY Study, which is like AIRTRIP, a randomized withdrawal study design, where patients have a run-in period of unknown duration to help maintain the blind for when they're randomized, and then they're followed for six months during the randomized withdrawal phase, and then there's a longer term extension period.

Paul Cremer, MD:
So to conclude, the main point that I want to make is that I think we should think of recurrent pericarditis as a prototypical organ specific auto inflammatory disease. And we should be emphasizing treatments that target auto inflammation, such as colchicine and the interleukin-1 antagonist. I think the questions that still remain are when to initiate interleukin-1 antagonist therapy and what is the appropriate duration of therapy. Thank you.

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