Dr. S. Allen Luis, MD discusses Recurrent Pericarditis in this Penn Presbyterian Cardiology Grand Rounds presentation. Dr. Luis is a physician with the Mayo Clinic and has been with them for the last ten years.
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Mm and you can see my slide, is that right? Yeah. Perfect. Good morning, I'm gonna introduce you to Dr Waxman I think just joined our Chief of cardiology here. Hi Dr Waxman, lovely to meet you. Nice to meet you too. So I get a little bit late here. Thanks for joining us. Looking forward to your talk. Thank you for having me. And as I told Samir if anyone has any questions or needs to bounce ideas off someone, I'm happy too because they are very lucky to have a group of nine of us to bounce ideas off and I recognize other groups may not have that many people with an interest in pericardial disease. So if ever anyone wants to bounce ideas we're happy to bounce ideas off them. So well thank you. That's a great offer and I'm sure people will take you up on it. Terrific. Thank you. All right, we'll give folks a couple of minutes here to join and then we'll we'll get started. Alright I know we've got a lot to cover today so um Alan, his folks are joining here, why don't we go ahead and get started. Um Good morning everyone welcome to cardiology grand rounds and it's my great pleasure today to announce Dr Alan Lewis from Mayo Clinic. Um Alan actually came to Mayo via um Australia and New Zealand where he did his medical training then came to Mayo Clinic for his cardiology training and has been on staff there for the last 10 years, Allen now serves as the co director for the pericardial Disease Clinic at Mayo Clinic, which I think all of us have learned a tremendous amount over the years um from folks like dr oh um and has really been a leader in the field of inflammatory recurrent pericarditis. It's something that I think we all have patients that we see and it's an exciting time because I think there are some new treatments that have come out, which we're very excited to hear more about and learn more about. Unfortunately, we're having some issues with the CMI department. Um so we're still working through that, we will keep track of all the attendees and hopefully we'll be able to um uh award CMI credit afterwards, but I do not have a code for today. So with that we'll we'll run things in a pretty traditional way. If you have any questions or comments, please feel free to leave those in the chat or the Q and A tabs and we'll leave the last 10 15 minutes here for a question and answer session with Dr Lewis. So with that Allen, I will turn it over to you, let you take over the screen sharing and um we're excited to hear your talk. Thank you very much and thank you for the invitation Doctor Kandahar to present this morning. Welcome to everyone in the grand rounds audience and thank you for your attendance this morning this morning. I'm going to be talking on recurrent pericarditis for the focus on the idiopathic and post procedural kinds of pericarditis. These are my disclosures. Um I do not receive any money personally from this from these companies but um the institution does receive money for my consulting activities with them. I'm going to be discussing off label usage of anna Kendra and canna Kenema biz. I'll one receptor blockers to balance that against the only available I. L one receptor blocker approved by the FDA on the market. And so through the course of this talk I really want to identify pitfalls in the assessment of patients presenting with recurrent pericarditis. And how do you confirm that they truly have an episode of recurrent pericarditis? I'd like to talk about the underlying path of physiology of recurrent inflammatory pericarditis in order to identify potential therapeutic targets. Then I'd like to talk about the indications for I. L. One receptor blockers, how to use them and how to apply them in your clinical practice. And last but not least, I want to talk about the indications for radical surgical Perkovic to me in the management of patients with recurrent pericarditis. And so I'd like to start us off with the case. This is actually the case of a 55 year old gentleman that I first met about 10 years ago when I was first on staff and I think caring for him really took me through the entire spectrum of recurrent pericarditis. And and really highlighted to me the various pitfalls that we can face as we treat this challenging group of patients. And so this gentleman had presented elsewhere with an initial episode of pericarditis. It was thought to be just like your usual acute pericarditis. He received appropriate treatment with naproxen and culture scene. He received a month's worth of treatment with both of these. The one month would have been short for a culture scene duration as we'll talk about later. But unfortunately six weeks after this first episode he had experienced his first recurrence of pericarditis. It was a florid recurrence of pericarditis. He had a significant pericardial effusion and elsewhere had a pericardial window placed. He did well following this for some length of time but 10 months later became quite short of breath was diagnosed as having a left pleural effusion. Saw the thoracic surgeon who did a thorough synthesis at that time and then two months after that because of this left pleural effusion, he was referred to pullman ology. Um They were worried about abnormal cells on history synthesis and as a result of that they did an F. D. G. Pet scan which didn't show any evidence of malignancy but in fact showed pericardial uptake of the para karniol enhancement consistent with inflammation. In his pet scan. He again was treated with a nonsteroidal anti inflammatory and culture scene and referred to see me in the pericardial clinic by the time I had seen him in the pericardial clinic thinks it's settled down and he was describing this occasional chest pressure which in his own words were if he thinks about it and not at other times now this was a fairly stoic gentleman. He would tolerate his pain pretty well. But you know he was relatively calm down, didn't have much for ongoing inflammation at that time and his examination was relatively unremarkable at that presentation. He underwent both cardiac camera imaging as well as echocardiography. Um I have chosen to show you the cardiac M. R. I. Here. First of all, the cardiac M. R. I. D. As you can see on the left here we have a T. One weighted black blood double inversion pre contrast image. And the reason I have this up is to highlight how thick the pericardium is. And you can see the pericardium anterior lee here and if you measure it, it measures up to eight millimeters anterior lee, so quite a thickened pericardium. The second image that we have is a. T. Two weighted adam, a sensitive black blood sequence. And what we're looking for here is for evidence of pericardial edema. And there is a hyper intense signal in the pericardium suggesting pericardial edema, although there is no accompanying myocardial edema. As you can, as you can see here the third set of sequences that we have our bright blood fats of breast post contrast lava signal. And this really demonstrates the hyper intense pericardium. And if we zoom out we'll be able to see a hyper intense pleura as well. And this was consistent with the Dema and inflammation of the pericardium. And last but not least, we have the delayed gadolinium enhancement sequence and we can see this really bright area of gadolinium enhancement along the anterior pericardium. All of this is consistent with inflammatory pericarditis with florida, inflammation and co existent pericardial edema. If we look at this echocardiogram, what I will point out here is the presence of apologies is the presence of ventricular interdependence um which is respirator physic in nature. And anytime you see that that should bring up the thoughts of is this constrictive pericarditis. He had the usual Doppler examination which showed marked inflow variation in the mitral inflow between respirator during the respiratory cycle. He had evidence of analyst reverses with the medial E. Prime velocity that was higher than his lateral E. Prime velocity. And he had evidence of hepatic venous flow reversals in exploration consistent with the diagnosis of constrictive pericarditis, given the presence of coexistence inflammation on the M. R. I. As well as these uh constrictive features on his echocardiogram diagnosis was that he had a transient constrictive physiology due to marked pericardial inflammation and edema rather than your traditional fi broderick type pericarditis. And so we thought that this was all inflammation related um I we initially opted to up titrate as non steroidal anti inflammatory and continue culture scene sort of thinking of the age old paradigm where we are taught in training to avoid steroids because of the risk of recurring pericarditis. Unfortunately with his ongoing inflammation he developed clinical signs of constrictive pericardial physiology with quite marked peripheral edema. And so I had no choice but to transition among two steroid and culture scene remembering that this was a transient inflammatory process. This resulted in resolution of constrictive physiology both in echocardiography as well as on clinical examination. But unfortunately as is commonly the case in these patients, it was difficult to be in the steroids and we were unable to be in his steroid therapy as a side effect of steroid therapy gained a significant amount of weight. We were unable to use an I. L. One inhibitor even though we prescribed it to him due to prohibitive costs and insurance issues. And so in accordance with the European Society of Cardiology guidelines at that time we instituted as a dia print and culture scene. Unfortunately, despite the institution of as a type and we continue to be unable to be in steroid therapy, He continued to have persistent inflammatory markers and there was a recurrence in this constrictive physiology. And so we ultimately referred him to a radical surgical park A deck to me and the reason I used to vote radical rather than complete is this truly needs to be a radical prostatectomy rather than a complete parakeet. Ectomy as we'll discuss a little bit later on and he's doing amazingly well. 2.5 years later off pericarditis therapy and clinically extremely well. And so let's talk a little bit about the assessment of patients with recurrent pericarditis. And my personal belief is that the most important thing in the assessment of any patient coming to pericardial clinic is a very careful and detailed history and examination. The reason that the history is important is it is important to revisit the story. It's very easy for us to review the chart and to fall into the trap that we're taught in medical school that if someone has had a problem before, that is the most likely diagnosis to re occur. And while that is true that that is the most likely diagnosis to re occur, we have to remember that other things can occur in its place as well. And so we need to keep an open mind retake the history. Is it classical? Is the pain there, does it last for a prolonged length of time without resolution in between. Is it pleasure Reddick, is it consistent with the natural history of pericarditis? I frequently in clinic have patients telling me yes, I have chest pain has been diagnosed as paracas itis, but the pain lasts for a minute. It goes away, then I may have another flare of pain later in the day, lasting a minute. Whereas the which isn't really consistent with pericarditis as opposed to pain that lasts for a number of days consistently until treatment is given. And so I also examined what are the triggers to their pain and what are their tapering regimes On examination. You want to look for features consistent with pericarditis. So you're looking for those features of constriction elevated J. V. P. You're looking for those features consistent with pericardial inflammation namely a pericardial rub. But what I find is incredibly important on my example is to exclude cost Akane writers and musculoskeletal chest pain as masqueraders masquerading as these episodes of recurrent pericarditis. And in my clinical practice in patients referred with recurrent pericarditis. I quite often find that there is in fact a masquerade er as a cause for the most recent episode of pericarditis. And so I personally pushed fairly firmly on the chest to ensure that there is no muscular skeletal component to their chest pain. And I find that about a third of patients presenting to see we are in this category of chest pain due to a different cause. Most often muscular skeletal, most often not responsive to traditional therapy. And quite often patients that benefit from some other means of therapy. But often with the help of the pain clinic, they may benefit from localized injections and nerve blocks to help treat their musculoskeletal or cost to contradict chest pain with episodes of pericarditis. This is an inflammatory condition. These recurrent pericarditis is and so often or really I'm looking for evidence of inflammation. So I do check inflammatory markers whenever my patients come back with a flair. And I'm looking for an E. S. R. And the crp either one will do crpf probably better than the S. R. But in clinical practice often we wind up getting both of these lab values. I think it's important to remember if someone presents with florid episodes of recurrent chest pain where your clinical instinct tells you that this is truly recurrent pericarditis. But A C. RP is normal. The crp can lag the episode of recurrent pericarditis by a little bit. And so what I'll often do if I'm convinced based on the story that this is recurrent pericarditis I will repeat the crp 24 or 48 hours later if it's negative. And I'm convinced that this is recurrent pericarditis. The next thing that I find is helpful as an echocardiogram and this and the cardiac M. R. I. R. A little bit. You know obtaining these should be based on the remainder of these factors. The echocardiogram is is extremely good at looking at the human dynamics. So I'm really looking on the echocardiogram for pericardial effusion and constrictive pericardial physiology in my patients with inflammatory pericarditis. They don't usually take all the boxes for constriction but they may take one or two boxes for construction and that really highlights to me the possibility of inflammatory pericarditis. The reason I believe in the value of both. The echocardiogram as well as the cardiac M. R. I. Is the echocardiogram really is the best human dynamic test it. Cardiac M. R. I cannot replace echocardiography for the diagnosis of constrictive physiology. In fact at Mayo Clinic we are so confident in our echocardiogram diagnoses of constriction that for patients with constrictive pericardial physiology we would be comfortable sending them to surgery without a human dynamic cath relying on the echo features cardiac M. R. I. On the other hand, it's strength is the ability to physically look at the pericardium. The pericardium is thin, it's difficult to physically see the pericardium on echo. So eco superior human dynamic test. Cardiac M. R. I really the superior test of being able to look at the characteristics of the pericardium and so on. Cardiac M. R. I am looking for thickening of the pericardium. I'm looking for delayed enhancement of the pericardium suggesting inflammation and at later stages fibrosis. I'm really looking for pericardial edema. I love those adama sequences where their diagnostic because the presence of edema and enhancement really helps me make that diagnosis. And I think for those of his interpreting cardiac M. R. I. It is important to be able to distinguish delayed gadolinium enhancement on the M. R. I. From the coexistence, epic cardio fat that surrounds these structures and so looking at the cardiac M. R. I. As we talked about and looking for pericardial thickness. I'm looking for pericardial edema and I'm looking for delayed gathering and enhancement and if we follow these patients serially with cardiac M. R. I. S. And I'm not advocating for regular serial imaging. But where there is a recurrence or where there's a big change in therapy you can see that there can be marked changes in the in the M. R. I. Findings in this patient on the left we had a pericardial effusion with a markedly inflamed pericardium and you can see over time the pericardium become much thinner and the pericardial inflammation has greatly improved. So let's talk about the definitions of recurrent pericarditis or the definitions of inflammatory pericarditis and the diagnosis of pericarditis relies on more than one feature all your patients will present with this pluralistic chest pain. But the presence of a pluralistic chest pain alone is insufficient to make the diagnosis of pericarditis per the guidelines. And so this is recommended to be taken in combination with either a pericardial friction rub E. C. G. Changes suggested a pericarditis or a pericardial fusion and the additional support of features of those that we talked about earlier with elevated inflammatory markers and evidence of pericardial inflammation by C. T. Or M. R. I. The guidelines also advocate this structure of defining pericarditis. They suggest an acute para academic episode is a single episode of self resolving pericarditis or resolving with treatment pericarditis. They then create these categories of incessant pericarditis, recurrent pericarditis and chronic pericarditis to describe inflammatory pericarditis is of various durations and last but not least. They describe constrictive pericarditis. This is traditionally thought of as a fibrous thickening of the pericardium, which will not resolve with with anti inflammatory therapy. But it is important when you're assessing your pain to think about the possibility that this may be a transient inflammatory process and to look for evidence of inflammation. Because as you saw on my patient earlier, treating the inflammation can resolve the constriction in that subset of patients. I must be honest and admit this. Many definitions of pericarditis are challenging to remember. It's challenging to divide people into these various categories. And so I quite like the newer classification that we and methodology that we think about this in which is you have acute pericarditis. And then everything else is complicated pericarditis. I would really like a categorization that has acute pericarditis, complicated inflammatory pericarditis. And then phi broderick constrictive pericarditis as a third category there. But for what I've got at the moment, acute and complicated seemed to make life a whole lot easier When we look at recurrent pericarditis. I think it's important that we remember that people with pericarditis have complications from the pericarditis. This is not a benign disease. And we can see uh cardiac tamponade in this database study occurring in 5.1% of patients And constrictive pericarditis. Remember this is a database in 1.7% of patients. This is really probably the transient inflammatory pericarditis is because an inflammatory pericarditis. We generally think that constriction is not a common complication of the truly inflammatory pericarditis is. But the reason I put these tables up is I want to highlight that the group of patients with recurrent pericarditis behave differently to the patients with a single episode of pericarditis that self limited and self resolving. And you'll notice that that incidents of cardiac tamponade rises from 5.1% to 8.9%. The diagnosis of constrictive physiology increases from 1.7% to 3.9%. And when we look at intervention rates we can see an almost doubling in the rates of para cardio synthesis and pericardial window formations in order to manage these people with recurrent pericarditis who are much more inflamed and are much more likely to have complications than your patients with the initial acute episode of pericarditis. I'm going to take a moment to talk about the path of physiology of this disease and the reason I've chosen to talk about the path of physiology of this disease is because I think it's important to understand the new therapeutic targets in this context here. And so really it all begins with the injured pericardial cell. The injured pericardial cell releases I. L. One alpha I L. One alpha binds to the tissue macrophage and causes an inactive I. L. One better through the inflammatory zone to become an activated I. L. One better. So you have I. L. One alpha from the damaged cells it causes production of I. L. One beta and then both your I. L. One alpha and your I. L. One B. To act at the capillary and ethereal sells really propagating inflammation. It causes increased white cell adhesion, neutrophils and mon aside infiltration and increased leak iness of the capillary resulting in a Dema. This in turn is a self perpetuating cycle resulting in more pericardial damage, more injured pericardial cells and all of this continues to repeat itself. I. L. One bidder will act through the I. L. Six pathway causing an elevated crp. I. L. One bidder will act through the cox pathway causing a fever steroid therapy really damps down this whole inflammatory process without without a specific target. Um The Kochs pathway is inhibited with the nonsteroidal anti inflammatories and culture scene blocks the development of tubules and propagation of this pathway through the inflammatory. The inflammatory um is the primary area where your culture scene acts in this pathway here. So let's talk about the treatment algorithm proposed by dr Huda Adler and colleagues in the european Society of cardiology guidelines. Unfortunately we have no North American guidelines for the treatment of pericardial disease but I think that this the guidelines provided by the european Society of cardiology. The management of pericardial diseases are excellent and definitely worth a read. And so the treatment algorithm here really specifies that our treatment of an acute inflammatory episode of pericarditis should start with aspirin or a nonsteroidal anti inflammatory in combination with culture scene. And in combination with exercise restriction. If that is insufficient to control your acute episode then move on to low dose corticosteroids with culture scene. If that is insufficient then low dose corticosteroids with culture scene aspirin or nonsteroidal anti inflammatory. So using all of the above in combination if they're not able to control this flair with that you then move on to I. L. One inhibition as a diaper in or I. V. Immunoglobulin per the guidelines and failing that the recommendation is to proceed to radical surgical per academic. To me I think that's a very logical stepwise approach in in the management of patients. I think it's important to recognize that the escalations in this pathway are generally for those people in whom the prior level of treatment was insufficient to result in resolution of their acute episode. And I think it's also important to recognize that escalation may be necessary if you're not able to wien corticosteroid therapy. So if you have a patient that has had a history of acute pericarditis but who does not have an acute flare at the present time there is no reason to escalate down the pathway. So just because you've given aspirin before the patient has calmed down but they have a recurrence of their episode. I wouldn't move up on the ladder just because they've had a recurrent episode I would start with aspirin all over again. I think the thing that's often forgotten is the importance of acute is the importance of exercise restriction, particularly during the acute inflammatory flares. So I think if we exercise when people are having an acute flare, this really does continue to flare up the pericarditis. So I think it's widely important that all of us as as providers treating patients with with acute or recurrent pericarditis really stressed the importance of exercise restriction during the acute inflammatory phase of pericarditis. And I think it's really really important to ensure complete resolution of the inflammation before we take the therapy. The most common problem that I find is that the patient still has ongoing inflammation, but we choose to wien therapy based on some preset algorithm for the number of days they received that therapy. In fact, what I would encourage everyone to do is if someone comes in with an inflamed pericardium is to recheck inflammatory markers, ensure normalization of the inflammatory markers prior to tapering down therapy because that may stop the need for you needing to go back on therapy with your patients. Now, those were the guidelines from 2015 and my colleagues around the country are proposed various alterations to this algorithm, particularly for United States population. I L one inhibition in the United States is licensed for recurrent pericarditis that is not a steroid resistant as opposed to our european colleagues where you can only move to immune suppression if peixe, I have uh corticosteroid resistant recurrent pericarditis. And so some of my colleagues would propose that immuno suppression be considered as the next step after nonsteroidal anti inflammatory and culture scene. And yet other colleagues would suggest that we follow the same algorithm but that surgical paracas ectomy should be considered on par with immuno suppression and at the same time as alternatives to each other. And really this is all in a state of flux as we get more data. I think these algorithms will be better defined over time. And I think this is a space that research is really going to change our treatment algorithm. So let's look at patients with recurrent pericarditis. And this was yet another database search published in 2021. And I think in patients with recurrent pericarditis, it's interesting to note that patients despite having a flare of pericarditis may not have been treated with any specific therapy. And a third of patients in the bottom in the bottom right here. It's also interesting to note that the treatment may have been underwhelming compared to what we were trying to treat. And the reason I say that his culture scene was administered in just 50% of patients. If we add up the numbers non steroidal anti inflammatories were administered in just 39% of patients And steroids and 30% of patients. And so what I really want to talk about is how can we achieve guideline directed therapy for the management of this patient population so that we can get true control of their disease. And so what I really want to start with here is culture scene therapy, Culture scene is widely available. We have a lot of data supporting its use but really it is an underutilized tool here. And so I really want to highlight first of all the icap trial which was worked from our colleagues in Italy Massimo Maceio and Antonio Ricardo. And I think that in this study they highlighted or recruited 240 patients with acute inflammatory pericarditis. So this isn't a recurrent population. This is an acute inflammatory pericarditis and they treated all patients with culture scene and placebo for three months. What I would really like to draw your attention to is the number needed to treat to prevent a recurrence. In this cohort was just four patients. So for every four patients you treated you prevented one recurrent episode of pericarditis. That number is startling And not seen in too many of our other recent pericardial trials. And so I really want to highlight culture scene for all patients with acute pericarditis, it decreased the persistence of symptoms at 72 hours, decreased the number of recurrences and decrease the hospitalization. All of you are going to say alan you're meant to be talking about recurrent pericarditis, not acute pericarditis. So I draw your attention to this study. The corpse to trial. Again done by my italian colleagues dr Massimo Massimo dr Antonio ricardo. And so in this group they did exactly that They took 240 page with significant pericarditis. These were people with at least two recurrences of pericarditis and they randomized them the culture scene and placebo and this time they gave culture scene for six months. Again. You see identical results to that in the icap registry number needed to treat of just five patients to prevent a recurrence. And you can see that this effect was significant in those patients with idiopathic pericarditis. But the effect was not significant in people with autoimmune disease with non idiopathic varieties of pericarditis. They noted that para cardiac effusion at presentation was an independent risk factor for additional recurrences, probably highlighting the severity of inflammation. So my summary for this slide is treat all patients with acute pericarditis with culture scene for three months. All patients with recurrent pericarditis with culture scene for six months. And the trials used culture scene at 0.5 mg twice daily if the wait was over 70 kg and once daily if the weight was less than or equal to 70 kg. I found this abstract presented by Dr. Claire Pete from the United Kingdom at the American Heart Association meeting and in this study they took 111 patients and looked to treat them with culture scene. These patients were all patients refractory to treatment. So they had had nonsteroidal and culture scene at the usual doses and culture scene at the usual dose was insufficient to manage their flare. They had another group of patients that were on steroids at enrollment into this retrospective study. And so what I'm first going to do is to look at the non steroid dependent group. So this group of 39 patients were on a non steroidal anti inflammatory and culture scene at the usual dose. In this study, they pushed up the dose of culture scene. So they aimed for a dose of three mg of culture scene per day. So three times what we're used to giving in doctor in maceio study. Even at the higher dose, They were not able to achieve three mg per day in the majority of their patients. And so they achieved a median of two mg per day of culture scene. They found that maximum dose culture scene really settled down these flares and only 10% of patients needed to move on to therapy using combination I. L1 inhibitor and culture scene. And none of the patients became steroid dependent. And so uptight iteration of culture scene managed 90% of the patients without needing to move them on to further therapy or steroids. What about the corticosteroid dependent population at referral. This was another 32 patients. They uptight traded culture seen in 84% of patients as the sole management. Uh 34% of patients got anakin ra steroid was discontinued in this population And steroid could be weaned with culture scene alone in 38% of patients. So really quite startling that with culture scene alone without needing to move on to further therapy you can get rid of steroids and one third of patients if you up titrate your culture seen Anna Kendra allowed weaning and 50% and as a type print in 11% there we all think about the side effects of this therapy. And so I think in terms of side effects of this therapy they discontinued culture scene and 4.3% due to G. I. Intolerance. So not bad for high dose culture scene and the self limited hepatic trans am in its elevation and 40%. And this in reality was self limited and not persistent in any of the patients going to change gears a little bit here and talk about corticosteroid therapy. The study again from Dr Damasio and Italy showed that low dose corticosteroids had a better event free survival than high dose corticosteroids. And so if using corticosteroids we should really be using low doses of corticosteroids. I think it's really important to recognize that if you commit a patient to steroid therapy, the tapers must be slow and the tapers must be incredibly slow over a number of months in order to achieve freedom from recurrence. If you win the patients like they have an asthma dose pack and you're giving two weeks of steroid therapy. It is highly likely that you will experience recurrent pericarditis. I'm going to change gears here for the last little bit and talk about I. L1 receptor blockers because they seem to be the new hot thing on the market at the moment and the topic of a lot of discussion. I would like to talk about anna Kendra Roland except and Kennedy mob as members of this class of I. L. One receptor blockers. So anna Kendra is a competitive I. L. One type one receptor antagonist. It blocks I. L. One alpha and I. L. One better. It's administered as a daily subcutaneous um injection and it was valid. It's used was validated in the air trip study that we'll talk about here in a little bit here. Rolen accept which is an I. L. One alpha and beta cytokine traps our traps the I. L. One alpha and beta before it binds to receptors in their landmark study. They gave her 320 mg loading dose subcutaneous lee followed by 100 and 60 mg weekly this was validated in the rhapsody study which we'll talk about in a little bit and is the only FDA approved agent for the treatment of recurrent pericarditis and then last but not least we have can Akina mob. It's a selective I. L. One beat a monoclonal antibody given it 100 and 50 mg subcutaneous lee every eight weeks and it did not undergo a randomized study. And the only data we have for this is case reports and so I'm really going to focus on the other two here because I can compare data side by side. And so the first thing I want to do is talk about the efficacy of I. L1 receptor blockade on treatment. And I think it's really important to remember that this is on treatment if they're not receiving drug recurrences may occur and we'll talk about that in a few moments. So, first talking about Anna Kendra and the air trip study here, what they did in their patients is they gave everyone Anna Kendra for eight days and then look for improvements in pain crp and pericardial effusion. And they noticed that the pain scores decreased very rapidly and the overall well being of the patients as scored by the patients improved from 5.8 at the start of the study to 1.6 a day 60. Very similar results in the Rhapsody study here, looking at the use of Roland except for recurrent pericarditis. You can see here quite starting willingly. That over the first week you can see a dramatic reduction in the crp and a dramatic reduction in the pain score reported by the patient. So really quite startling response to therapy on treatment here, looking a little bit closer at the Air Trip study here. This was anna Kendra for two months. Nonsteroidal and steroids were allowed to be withdrawn. Culture scene withdrawal was optional. They recruited 11 patients to the anna Kendra arm, 10 patients to the placebo arm and treated them for six months. The recurrence rate for placebo was 90%. Whereas the recurrence rate for those patients on Anna Kendrick was 18.2%. So quite a startling difference with a very significant p value. They're really highlighting the efficacy of this drug in the management of patients with recurrent pericarditis Rhapsody study. Again, very similar results here during the run in period. So they had an initial 12 week period in which everyone got Roland accept and had their background therapy withdrawn. In this study they had a very small number of patients in whom Roland was not tolerated or Roland except was not effective in treatment. So three patients didn't meet their criteria for response. Four patients were discontinued due to adverse reactions to patients. The invested data decided to discontinue and one patient discontinued for some other reason. The median time after discontinuation of Roland except to the first episode of pericarditis was 8.6 weeks in the placebo group. And if we look at the two curves, we can see that 7% of patients or to patients rickard in the role on a set group. But we had 74% or 23 of the 31 patients recurring in the placebo group. Once you commence an I. L. One receptor blocker. In both these trials, they moved to withdraw background therapy. So if we look at the ana Kendra trial, they began tapering at day eight, they allowed six weeks for tapering of nonsteroidal and corticosteroids. Culture scene was withdrawn in about half of the patients and the administration of culture scene did not seem to affect the rate of recurrence In the role on a set group. They allowed withdrawal again after eight days of stabilization. They allowed 10 weeks for withdrawal. But they required that steroids nonsteroidal and culture scene were all withdrawn. There was no tapering regime specified and they report that therapy was withdrawn in about eight weeks in the majority of patients. The question I commonly get asked is how long do I treat a patient with recurrent pericarditis for. And that really is a difficult question that I feel is unanswered. If we look at the air trip study, the total duration of therapy was eight months. We were involved in the Iraq registry looking retrospectively at real world data using anna Kendra and the median duration of therapy and that study was six months followed by a median taper of three months and nine months of total therapy. If we look at the colonies have faced to trial that was six months. And if you look at the rhapsody clinical trial, they treated patients for a median of nine months at the time of reporting of that study and then moved on to a long term extension phase where people received significantly longer therapy. The failing of the I. L. One receptor blockers that I see is really the ability to withdraw treatment at some point because of the recurrence risk. And so if we look at the Iraq registry headed by my colleague, Massimo Maceio, in which we were involved in the median duration of treatment with Anakin River six months. They defined that if people got more than three months of therapy, it seemed to result in a greater freedom from recurrence and the longer we treated patients for the lower the risk of recurrence. But I really want to highlight that even in the three month or more group, you're looking at a 50% recurrence rate, which is really quite a lot. But this is a difficult bunch of patients. If we look at the rhapsody long term extension period, they treated patients with a median duration of 18 months in the us and 27 months in non us patients. The reason for the difference was the time that the FDA licensed the product in the United States. They mandated an 18 month decision point where the clinician decided whether to continue treatment or whether they should discontinue treatment at that point. And I think this really highlights that withdrawal of therapy even after such a long course of therapy resulted in quite a significant rate of recurrence. As if you can see here, We can see that 75% or six out of the eight patients in the off treatment developed a recurrence with the time of 11.8 weeks to recurrence and just 3% of the patients that continued on therapy. Um in the Roland group developed a recurrence although that recurrence it was associated with the four week interruption to therapy. So what about tapering therapy? Um as was suggested in the Iraq registry and the Iraq registry really showed that when we use an in camera that a tapering tapering regime may be helpful in the management of these patients. And patients were divided into tapering of no tapers, tapering of less than three months and tapering of more than Three months. And we found that the longer the taper instituted, the greater the freedom from from recurrence. But again I point out on these bottom curves here, your freedom from recurrence is just 50% on the top curve. It's doing better than that. What I would like to highlight is that Roland tapering was not studied in the rhapsody study and so we have no data to talk about this in Roland accept patients when I start an I. L. One receptor blocker. I'm looking at institute I'm looking at checking Hepatitis HIV and tuberculosis status before I institute therapy. I want to make sure they're not pregnant that they haven't had recent live vaccines and that their vaccinations are up to date. Most common side effects of these. Therapies are injection site reactions and infections, particularly upper respiratory tract infections and Disl epidemiology frequently gets worse on this therapy and so needs to be monitored. Potential new agents that are in the pipeline, pharmaceutically manufactured cannabidiol that block I. L one beta I. L six and L. P. R three and Pro I. L. One beta M. R. N. A. And these have shown promise in mouse trials. Again shown as the american heart association meeting and in the mouse model we can see that it decreases pericardial effusions and decreases pericardial thickness. Were actually involved in a Phase two clinical trial recruiting patients with recurrent pericarditis who have had at least two prior episodes with idiopathic or post procedural pericarditis into this trial, looking for patients with pain and crp as a manifestation of an acute flare. And so really this may be another potential therapeutic target in the longer term pending results of clinical trials. I'm gonna take a couple of minutes here to talk about surgical para Kadek to me, before we wrap up here and I think what the slide here really highlights the efficacy of surgical para Kadek. To me, I think we need to remember that surgical paracas ectomy for recurrent pericarditis is a completely different beast. A surgical paracas ectomy for constrictive pericarditis. Constrictive pericarditis, you have a thick adherent pericardium that's difficult to remove. That is associated with a significant risk when we talk about recurrent pericarditis is these tend not to be adherent to the adherent to the underlying heart and tend to be easy to remove as therapy. My surgical colleagues tell me that these are much easier to remove and what they would call a joy to remove as opposed to doing a constrictive uh para cod ectomy operation. The outcomes of this are incredibly good. The we had two patients with major morbidity following the operation. So the majority of patients did extremely well. Um it was really important to excise the para key item in its entirety. And um Para Kadek to me, really decreased the recurrence of symptoms and had fewer relapses compared to the medical management arm. We can see on the left top there the Kaplan meier curve showing excellent survival out to 14 years on the right hand end of the of the survival curves. There's a really excellent survival comparable to the medical management group. And when we look at freedom event free freedom survival in this patient population, we can see that the surgical group out to 14 years had a 90% event free survival as opposed to the medical group consistent with the I. L. One receptor blocker data where there is only a 60% or so event free survival. And so I think it's really important that surgical para que decked AmIS are performed by expert pericardial surgeons. And I think I need to highlight this notion of the traditional complete para Kadek to me. So I trained in Australia and new Zealand I worked in a number of different institutions and the traditional complete paracas ectomy involves removal of the anterior and inferior pericardium alone while you leave the posterior pericardium behind. That is insufficient. In patients with recurrent pericarditis and in patients with recurrent pericarditis you must get all the pericardium and at mayo clinic from time to time we will do this on cardiopulmonary bypass in order to allow us to be able to take the pericardium away in its entirety because it is absolutely mandatory that we must perform a radical prostatectomy removing the entire para card including the posterior pericardium and the traditional complete paraquat ectomy alone is insufficient. So in conclusion I think it's essential that you re confirm the diagnosis of recurrent pericarditis every time your patient represents and beware mimic is particularly muscular skeletal chest pain. I think it's important to ensure complete resolution of pericardial inflammation. Prior to tapering medication. I think culture scene is an under used therapy that should be used in all patients with inflammatory pericarditis. Unless there's a contra indication steroid. Use escalation from non steroid steroid should be used with caution and if you choose to pursue that you must taper your steroids slowly. I l one receptor blocker therapy is effective but may be associated with a high rate of recurrence following discontinuation of therapy and radical surgical paracas ectomy is effective treatment performed and experienced hands in the management of recurrent pericarditis. Thank you all very much. Alright. Fantastic talk Alan thank you very much for that. Excellent overview of pericarditis. Outstanding. Thank thanks so much. Going to take some questions as a couple in the chat. Yeah, I was just gonna say I apologize the cmI credit we're still working on so I don't have a code for everybody. Um today we will keep track and hopefully be able to uh war those afterwards um and hopefully have this issue resolved in the near future. Um harvey, do you wanna start with some questions and then we'll go from there. Sure. I I just had myself too and then we take a couple while you can look those up in the Q and A. But alan um question and maybe a comment. One question is I think you answered it partially. What kind of work up do you do with the onset? To be sure it is. In fact idiopathic. I'm just curious what your work up is to look for other ideologies. Number one. And then the other comment I had is, you know, after listening to this wonderful talk and all the options. I think at the end the real question is as you I think sort of alluded to is is just surgery. The answer. I mean most of these people just need an operation early on rather than going through all these treatments, relapsing etcetera etcetera. Maybe maybe that's uh some change in the algorithm is curious your thoughts where you are with that now, those are great questions there, harvey So in answer to your first question, how much work up for an autoimmune cause generally I initially based this on my history and examination. Do they have any red flags? That that really flag? Oh this person has inflammatory disease. Do they have a strong family history of autoimmune disease? And those are things that that sort of raise my concern raised and make it more likely for me to pursue and an antibody work up for an autoimmune cause to be perfectly honest with you, we received quite a biased referral population here. And so routinely we do autoimmune titus. So we do a N A D N. A. We do anchor, we do rheumatoid factor and we do anti CCP antibodies fairly routinely in all our patients. We don't pursue a work up for viral causes because we find that unhelpful because the majority of patients test positive to a number of viruses and you don't know what the causative etiology is. Um I have to say more often than not, an autoimmune screen crops up abnormalities that are of no clinical significance when we talk to the rheumatologist. So I think the most helpful thing in terms of auto antibody screen and making the diagnosis of idiopathic pericarditis is really the history and the examination. We also would routinely do on my Loma screen. You know I think we're looking for fairly rare things and I have not seen a positive myeloma screen yet. But again, because of the referral population and the unusual nature of our practice. We we do do on myeloma screen. But I think the diagnosis of idiopathic idiopathic nature of the pericarditis is really based on clinical judgment here. To come to your second question about, Sorry harvey, did you have a question or comment to that before I go ahead? I'm sorry, surgical thoughts. Yeah. So you know that you know what you bring up is exactly my concern there harvey that at the moment we don't have good treatment that allows these young patients in their thirties and forties to come off treatment. And we have this issue that these patients may be on treatment in the long term or lifelong. We know that short term therapy alone may be insufficient and patients are on therapy long term. I think the issue with these drugs or the issue partially is in the mindset of the patient. The patient wants to avoid adam, adamantly avoid the need for cardiac surgery. And so more often than not they are willing to do anything possible to avoid surgery. And I think that's why we come to the nonsteroidal the the steroid, the um uh immuno suppressant before we get to the surgical prostatectomy. My colleague and you know when I see these patients in clinic, I pull up the Iraq data that we were involved in and have a very frank conversation with our patients that in about half the patients I'll get you off treatment in the other half of the patients. I may be unsuccessful. I haven't had access to the rhapsody lT data up until this point. And so I might be even more pessimistic with my patients in future and say maybe a third of people will get off treatment here. And my colleague joo would strongly advocate for the presentation of immuno suppression and cardiac surgery side by side rather than cardiac surgery being the last resort. The issue that we face is that a number of our colleagues internationally. And I found this at previous meetings particularly with my European colleagues is that they feel that surgical pro Codec to me is barbaric and and extreme and you know that that's sort of the take that that our colleagues have have received because they feel that I. L1 inhibitors are so effective in treatment. But I think in saying all of that, I think that radical surgical paracas ectomy done well by an experienced surgeon who knows to take off all the parakeet um and is experienced in doing that is worth its weight in gold. Sorry. Long winded answer to your question. Great. Great. Great. Thank you so much. You want to take some of the Q. And a questions a few in there or whatever you have. Um No. Perfect. This question. This issue comes up patient presents with symptoms more consistent with pericarditis. But then on M. R. I imaging you see a combination of MyO pericarditis. Does that change your management if you see myocardial involvement on an M. R. I. Scan? Excellent question Samir. And you know that winds up being a difficulty a lot of the time. I kind of work on the principle of what is the predominant disease pattern being seen. So it's quite common when we look at these Maya pericarditis is that you have a very inflamed pericardium and a thin layer of inflamed myocardial underneath. You know sort of in the adjacent layer of myocardial. Some sub epic arial enhancement although not in keeping with the with the package insert for all these agents. I am comfortable treating maya pericarditis as pericarditis. Where the predominant pathology is paracas itis. If the predominant pathology is pericarditis with a little bit of, sorry if the predominant pathology is myocarditis with a very small amount of pericarditis then I would treat to the myocarditis and I would avoid treatment that's pericarditis specific. Does that answer the question there? No that's perfect. Um This question I know that you've discussed but just to go over one more time for everybody. How long do you treat? The first episode of pericarditis with Nsaids or culture scene. So typically Samir. What I do in the first episode of pericarditis. Is I would treat typically with two weeks of a nonsteroidal followed by a taper of the nonsteroidal over the next two weeks I typically use um ibuprofen because it's easily available over the counter and comes in 200 mg tablets. So I I tend to use 600 mg three times a day. Use that for two weeks and then paper for those patients that come and see us in hospital. Those patients usually have rip roaring pericarditis with a huge amount of inflammation and so I worry that that alone is that duration alone is insufficient to control their pericarditis. And so my duration of therapy is really guided by a repeat C. R. P. So I say in two weeks I want to see a repeat crp. If that crp is now in the normal range. I will taper you if it's not in the normal range I will give you another two weeks at your same dose before I'll taper you and if I'm giving another two weeks I then asked him for another crp to prove normalization before I taper. In terms of culture scene I tend to treat culture scene based on that I cap data in which they treated with culture scene for three months. However if the patient has required an extremely prolonged course of non steroidal where the nonsteroidal runs into that three month limit, I may consider extending out culture scene just um just so that I have some over overlap of therapy and I'm not stopping both therapies at exactly the same point. I acknowledge that there is no data for me prolonging out culture scene beyond three months. And I usually do not but I do keep that option in the back of my sleeve. Knowing that culture scene and recurrent pericarditis was given for six months. Allen is for patients that respond to culture scene and have um let's say they've had now their second or third episode but each one responds to culture scene. Is there a role for long term suppressive use of culture scene? That's an excellent question. Samir and one that's not supported or refuted by the guidelines. In fact I have a couple of patients that are in exactly that that category. The one that really rings to mind was I tried a number of times she was on nonsteroidal and I think even steroid and culture scene for a length of time and she would do fine coming off the nonsteroidal should do fine coming off the steroid. But every time we took away her culture scene shortly after that she would have a flare of pericarditis. And in her she actually herself noticed that it improved her rash. And so she came to me in clinic one day and said dr lewis I completely understand that we want me off treatment. But every time we stop culture scene, I get this flare of pericarditis, I would just like to stay on culture scene and she's done well now for a number of years on culture scene. I recommend that we check a cbc and liver function test on an annual basis to ensure stability of the disease to ensure that we have no adverse effect related to the culture scene. But I do have a couple of patients in whom um I've chosen to pursue this off label indication because every time I withdraw culture scene they have a recurrent flare. Sorry, long winded answer to what was a fairly simple question. But I do have to acknowledge that there is a lack of data in this in this area but I have found it successful in the patients that I have had them on. Um One more question if you have a couple of minutes here and the Q. And a tab that came through, what is your approach to patients who are status post radiation to the chest wall and its treatment different prognosis different in those patients. That's an excellent question. Um They are a difficult bunch of of patients to treat. I tend to follow that european society of Cardiology guidelines. I start with nonsteroidal anti inflammatories and I start with culture scene in that patient population there's no particular order. You know, the inciting factor should be similar to a post para cardi artemis syndrome where the radiation has sensitized the body to the pericardium, resulting in an inflammatory process. So I tend to follow the usual algorithm often in those patients they need steroids for their cancer therapy and so often steroid may be instituted earlier on by the oncologist. And if that were the case then steroids then I would be guided in terms of my therapy in conjunction with the oncologist as to whether they're happy with the nonsteroidal use, whether they're happy with using steroid what their preference would be. And then on top of that I do add in culture seem to that patient population because I believe although not included in the trial, that there is a treatment benefit to culture scene there unless of course contraindicated sometimes when you're giving chemotherapy, the oncologists don't want culture scene on board and in those patients I I put their cancer therapy ahead of the pericardial therapy because that's the most life limiting issue there. Harvey you want me to turn it back over to you for any last questions or closing remarks. Sure, I'm happy to. First of all, what a wonderful talk. Dr Lewis thank you. Is I think your analysis of the data was wonderful and extensive and I think but I takeaway also is that your clinical experience and judgment is a large part of guiding these therapies which are complicated without a lot of strict hard guidelines in some areas. So along those lines, I appreciate your your offer that people call you for some of your thoughts and managing these difficult patients and you may hear from some of us along those lines. I think that your your experience and judgment is invaluable in these areas where certainly there are no clear guidelines. Again, I can't thank you enough for this wonderful talk and education and area that a lot of us don't have a lot of experience. I don't see that many cases but I certainly learned a lot today. You know we all did so thank you for taking the time to meet with us, greatly appreciate it. And uh again thank you so much. Thank you very much. Dr waxman and as um as dr waxman said earlier I'm happy to you know I'm lucky that we work in a para cardio clinic with eight colleagues to bounce ideas off. And so if any of you have challenging patients and you want to reach out for a for a second opinion or just to bounce some ideas off, I'm happy to take questions or or a phone call at any time. Thank you. Thanks linda. Thanks Sameer everybody have a great day. Thank you. Thank you very much everyone. Thank you again Alan take care
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