 Okay, I think we're gonna try and get started. We have three presenters today, so the first one is Barbara Borosco. And then we'll have Bonnie Keong presenting Giant Cell Urterata Spectrum in Future and then Tom Ober presenting cryopyrin-associated periodic syndromes in the eye. All right, good morning everybody. All right, so this is a case that came up when I was on Peds and then again on Neuro and it wasn't something that I had really heard of before and it kind of started with a, here we have a consult for you. It's one of your patients that you file for muccal wells. We need you to kind of roll out her aseptic meningitis and papillodema. And I said, oh yeah, of course, muccal wells. I'll be right there. So this is a 10-year-old girl who at birth was known to have a chronic waxing and waning urticaria, seemed to worsen in the winter and occasionally it was associated with conjunctivitis and arthropathy. It had sort of been persistent for three years. She had sort of seen a slew of dermatologists and other folks, made her way into a Peds rheumatologist and allergist and he said, you know what, let's check your ESR. That came back elevated and he became concerned for a CAPS type of syndrome centered to the NIH where they did genetic testing and she came back with this mutation. We'll get to that mutation in a little bit. At age eight, she started to have worsening arthritis and headaches, sent her to see the pediatric ophthalmologist where a mild anterior uveitis was noted in the left eye. And no treatment was really started. It was very mild, just sort of rare cell. But then later in the year, her headaches and arthritis worsened. They did a spinal tap and her opening pressure was elevated at 31 and then she came back to see us in clinic and then she had a papillodema at that time and that anterior uveitis was persistent. So she started on a medicine called Kinneret and then a few months after initiation of the treatment, her aseptic meningitis, papillodema and uveitis had resolved. So a year later, she's doing okay. She's still having sort of flares. They had to change her medication and regimen around a little bit. And unfortunately, she's recently been detected to have decreased hearing on the audiogram. And then that's when she was switched to this new medicine. Oh well. So this is, sorry, I don't know why that copied so bad from Willow on the right eye, but her visual fields there look pretty good. This is when she's now seen us in neuro opth to just take a closer look at the nerves and we think the nerves are looking pretty healthy. Visual fields are full. Her RNFL is pretty full and there's her nerves. So she, unfortunately, to complicate the issue, she has kind of funny looking nerves, this coupless disc and her mom has the same exact looking nerves too. And then the family history. So her mom who's with her previously had been diagnosed with Bichette's disease, not related to the eyes, but to just severe recurrent mouth and throat ulcers. But she also had sort of lifelong recurrent conjunctivitis that she sort of just treats herself with over-the-counter allergy drops. She said she saw a UVitis specialist at one point in time and was told that she had a completely clean eye. And then when her daughter was tested at the NIH, they tested her and she carries the same mutation as her daughter. And then there's also a maternal uncle that has sort of an undiagnosed serum negative rheumatoid arthritis, but he has not been tested. And then this is sort of late breaking news to me. Dr. Vitale grabbed me in the hallway yesterday and said, you're talking about muckel balls? I have a patient with muckel balls. I think it's the same patient, but it's not. So this is a 28-year-old woman that was referred to Dr. Vitale for erupt onset of redness, pain, and itching in the right eye. She also had recurrent conjunctivitis or decarious, sacroiliitis, fatigue, and headaches. And it was her right eye that was affected. The vision was a little bit down. She had more significant cell and flare in the anterior chamber, and she had a pretty prominent vitritus and the nerve was normal, but she had an epiretinal membrane. And then he said she had this kind of white, creamy lesion inferiorly in the far periphery. She was also treated with Kinneret and her eye symptoms resolved. And now that same patient has a 10-year-old son with her to carry her fevers and articular symptoms. And so this family also wound up getting tested and they had another mutation in this NLRP3 gene, which I'll get to, it's a different mutation, but same gene. And that was, they actually were able to figure out what was going on with them. Okay, so cryopyrin-associated periodic syndromes. So this represents a family of auto-inflammatory disorders, which is different than autoimmune disorders. Or in an autoimmune disorder you're producing an actual antibody that's attacking the rest of your systems in this spectrum of disorders. You're just having this marked inflammatory response that's not really necessarily to anything in specific. So this, the caps represents a spectrum of what used to be considered three different diseases. The first is familial cold auto-inflammatory syndrome. The second is muccal wells. And the third is neonatal onset multi-system inflammatory disorder, also known as NOMID, which is that's what's called in the States and then in Europe it's called chronic infantile neurologic utaneous articular syndrome or SINCA. And so I'm gonna say this used to be considered three separate diseases until 2000 when the gene was identified. And now they recognize that it's really all of the same spectrum of the disease with just sort of different severity leading to different clinical presentations. So the common symptoms for all is a non-puretic urticaria. And that sort of helps rule this out from sort of like a cold induced urticaria or familial Mediterranean fever or other things that cause rashes that are really itchy. They all have conjunctivitis, which usually occurs with a flare. They all have general malaise, headaches and joint pain. And this is unfortunately a poor little guy that has NOMID or SINCA, the worst kind and it's his mom that has sort of developed his website to sort of reach out to everybody and try to inform him because it's becoming more well recognized. Okay, and then a lot of them have flares following exposure to the cold. So nearly all patients with the less severe form, many patients with muccal wells and some with the NOMID SINCA. And it's not understood why the cold causes these flares. Nobody has really been able to identify what exactly it is that's making that happen. So like I said, we're thought to have three distinct diseases and then since we sort of know that's more three phenotypes with the same disease. And this NLRP3 gene is found on chromosome one. It's mostly inherited as an autosomal dominant disorder. There are sporadic cases and they've identified over 118 different mutations now and they all seem to lead to this missense mutation that leads to gain of function. And this is where the name comes from. It's nucleotide binding, leucine rich pyrin containing three gene. It was previously known as cold induced auto inflammatory syndrome one. And the kicker of it all is that it codes for cryopyrin. So you have a gain of function that leads to increased cryopyrin. So cryopyrin regulates the innate immune response. It's expressed in monocytes, neutrophils and chondrocytes and that becomes a little more apparent in the more severe spectrum with their joint changes. They form these intracellular complexes called inflammasomes which do a lot of things but the crux of what happens in this disease is it activates caspase one and that cleaves pro-interleukin one beta into its mature and activated form and interleukin one beta is pro-inflammatory. It's an endogenous pyogen which is why they all have these recurrent fevers. And then that also acts in the liver to stimulate hepatocytes to make serum amyloid A and that'll come back to bite us later too. Here's just sort of a diagram saying that here's cryopyrin and here's the pyrin myrnosterin is what's found in familial Mediterranean fever. That's what gets dysregulated. They both wind up coming through the same pathways. You activate pro-caspase. You get dysregulated apoptosis. So they find that the macrophages undergo apoptosis too quickly and release some of their inflammatory cytokines and then neutrophils have dysregulated apoptosis and don't turn off and continue to sort of release their effector chemicals. And then here's the interleukin one leading to increased amyloid A and basically everything leads to pro-inflammation. So it's a huge pro-inflammatory state. This is pretty rare. They did a recent study in France and found that the incidence was about one out of 360,000 and of those, muccal wells was the majority with the synconomad being the least common. 10% of them they couldn't really characterize meaning that they didn't have enough data to put them anywhere specifically on that spectrum. And in Germany they did a similar study and found that every year between two and seven children of all children less than the age of 16 were getting diagnosed with a CAPS syndrome. In North America it's one in a million for the familial cold on the bottom of the screen got cut off. So it's very rare, similar incidents in Europe that's what the bottom of that slide says. Okay so now if we go through the individual syndromes so the familial cold autonomic syndrome. So the diagnosis requires four out of the six of the following. So exposure to colds remember these guys are really sensitive to the cold. So I have a rash in one to two hours and the urticarial rash that we saw. Those are sort of migratory papules that will clear of their own in about 24 to 48 hours. Remember they don't itch. Low grade fevers, joint pains, there's the conjunctivitis that we might see and then some more nonspecific kind of problems. These guys carry an excellent prognosis. It's really more of an inconvenience than anything that's gonna cause them lifelong disabilities. And that's supposed to, you know, the next worst disease is gonna be muccal wells. This is what our two patients were diagnosed with. It's the most common of all three and some people will say it's pathenomonic. If you have conjunctivitis and progressive sensorineural hearing loss. So our patient definitely had conjunctivitis and then she was recently determined to have this hearing loss. Unfortunately, her most recent hearing test was only a couple months ago and the one before that was five or six years ago. So nobody's sure if it actually started before she started treatment or if it occurred while she was on treatment. And with these guys, the flair is not necessarily triggered by cold. And then because of what we saw with the Interleukin-1 stimulating the hepatocytes to make serum amyloid, 25% of these patients wind up getting amyloid dosis and a high percentage of them wind up getting an aphropathy syndrome. And they have joint pain without radiographic changes which is contrasted to the nomencinka where they have pretty marked joint destruction. And it was until recently, we thought it was just conjunctivitis that you would see with muccal wells. But there's now been two or three papers in the rheumatology literature of patients presenting with corneal haze, uveitis, which unfortunately has never actually clarified as if it's anterior, posterior, pan-uveitis because it's, I don't know, it's not in the papers where you can find it. They just give them one sort of blanket term for uveitis. And there's been three or four patients now with episcleritis and then a handful of patients with aseptic meningitis and papillodema like our patient. And their prognosis overall is a little bit worse because of the amyloid and the deafness. It's a little more disabling. Oh, I'm sorry. So the common for all of them is conjunctivitis and the rash, the urticaria. Yeah, so unfortunately it's the same thing where it's a rheumatologic paper and they just call it corneal haze and they don't really specify. But in some of the nomencinka papers there's a little more in depth and they have postulated that it's from the amyloid. They've also postulated that it's from just chronic inflammation. But nobody knows and there's, the end result is haze and some of the patients actually have stromal neovascularization. Okay, so this is just a paper that's showing the, these guys looked at what were the risk factors for severe mucle wells. It turns out that it was being a woman and presenting with deafness at the first presentation was the worst risk factor but this is what they were seeing. So they saw conjunctivitis in 70%, uvitis in 13 and papillodema in nine. They don't say if that's the same patients and it's not, and I assume this is linked to aseptic meningitis but they didn't specify that. And again, here's just sort of a blanket uvitis term. And here's another paper that, this is really the only other paper that found severe eye findings and so they saw, they had a family of four. Episcleritis was three out of the four, papillodema was in three out of the four and the deafness was in three out of the four. So again, sort of linking worse in, worse hearing sort of links to more severe disease and then going on to the worst disease in the spectrum, this NOMID and slash SINCA. So before they sort of got to this newer generation of treatments there was 20% death before adulthood just because it has such severe manifestations. As of 1997, a review of the literature only found 54 reported cases that never has not grown much since then. And with these folks, they find that as opposed to the autosomal dominant it's more sporadic just because most of these patients aren't living to adulthood and they're not able to reproduce. And so it tends to be more sporadic and then they've also found that these people tend to exhibit more sort of somatic mutations. So testing them at one day might find the mutation, testing them at another might not depending on what cells actually get tested that day. They may actually exhibit signs of inflammation in utero and that picture that we showed of that little guy with the rash, the mom said that when she delivered him the placenta came out and it was like a sort of a green stinking kind of mass and it was, and the doctors were like something's just not right and poor kid's been sick since then. Most of them are born when they come out of the womb with a rash already. And their triad that sort of puts them in their own diagnosis is urticaria, arthropathy and CNS involvement. And these guys, unfortunately, their bones have distinct radiographic changes. It's not an inflammatory type of reaction. It's this weird cartilage and if we remember back that gene is expressed in monocytes, neutrophils and chondrocytes. And so that's where we think this is all coming from. And then the CNS was aseptic meningitis, elevated ICP, deafness at a very young age which is in contrast to the mucle wells which usually occurs in adolescence. And they unfortunately also have a lot of strokes and seizures. And then this has been well described with nomenon syncoda, conjunctivitis, the keratitis, corneal haze, uveitis, pan-uveitis, vitritus and papillodema. And so those are the knees. And you can see here, this is the epiphyseal plate that's just massively hypertrophied and if they looked under the path it was disorganized and that's actually the patella. So that's pretty distinct from mucle wells. I'm pretty severe. And then here's a, this is in archives of ophthalmology about 12 years ago now and they looked at 32 patients. And they were really looking at trying to distinguish you know, what are the characteristic features of synchonomid and then also to contrast that between JIA and so we'll get to that a little bit later. But sort of protean manifestations in the eye, bank keratopathy, stromal infiltration, corneal neovascularization. What they were very surprised about was that despite the sort of chronic uveitis they didn't see any patients with glaucoma. And then here's the posterior findings that they saw. So vitritus, vasculitis, macular edema and then just sort of a whole bunch of different problems with the nerve. So the treatment, once they sort of figured out the pathway, they thought, why don't we just start using some of these drugs that target interleukin-1 beta. And so the first one that sort of, and the most popular one is, and a kinder also known as kindereth. This is what both of our patients were placed on. It's a interleukin-1 receptor antagonist. It was actually first developed to treat septic shock because they found that a lot of the problems with septic shock was actually sort of the endogenous factors that we were producing is to shut that down. It didn't work so hot for that but they noticed that some of their patients that had rheumatoid arthritis were like, I feel really good now. And they said, well, let's try it. So it's been a very, very successful treatment. It's actually been shown in a few papers to not only halt the disease, but there's been reported cases of reversal of hearing loss, reversal of nephropathy. Unfortunately, it requires daily injections, which is not the easiest thing to do on some of these younger children. Volanosept is a IL-1 trap that hasn't really come into the mainstream yet, but this next one, kinumab, that's a fully human monoclonal antibody and that's been great because that only requires an injection every eight weeks. Unfortunately, it's much, much more expensive than the kinderette, but our patient who is, there's this question of whether or not she was sort of failing on the kinderette. She was switched to this medicine and seems to be doing a little bit better and she's definitely happier because she's only getting a shot every once every two months instead of every day. So these, introduction of these has, you know, increased the lifespan and the nomid sync of patients and made everybody sort of a much happier patient and speaking to the mom about our patient, you know, she was like the fifth percentile in the height and weight and then when she started kinnerette, she sort of had this major growth spurt and it's sort of catching back up to her peers. So it seems to be really sort of revolutionized the treatment for these folks. And so a quick differential for us is a uveal meningiocyndromes, which we all know and love. And you know, here's our patient whose mom was actually diagnosed with Bichette. So, and then the other big differential, which used to be more of a problem for just the syncha and the nomid, but I think that as we sort of learn more about Mucklewell's presenting with these eye manifestations it's gonna become sort of more important for us. And this is that same paper from 2000. Basically the big things that they noticed where the eyes typically are more red and synchronomid whereas JRA, we typically associate them with a white and quiet eye. And there's much more stromal keratopathy with the synchronomid patients. Okay, so just what I got out of this was this is a very rare disease but can basically present with any eye finding that we can think of. And as the diagnosis becomes more well known and people start to recognize that it's not just these really sick kids with synchronomid that are gonna have eye findings, sort of like how this one patient will wander away to us. You know, it's becoming more evident in the rheumatology literature that they're gonna require more eye screening. So this is something you may be asked to screen for in the future. And just also to keep it in the back of your mind if you see some weird patient that has these weird findings because not all of them present the same way and even within the same family and the same mutation they can have completely different presentations. So just something to keep in the back of your mind. Okay, thank you.