Chapters Transcript Video Macrophage Activation Syndrome: Calming the Cytokine Storm It is my pleasure to introduce Dr Soulsby who is an assistant clinical professor of pediatrics at UCSF and a new attending in our division of pediatric rheumatology. He completed his undergraduate degree in physiology at the University of Arizona in 2012. He then received his medical degree from ST Louis University in 2016. Dr. Soulsby came to UCSF for his general pediatrics internship and residency, followed by his pediatric intelligence fellowship here, staying on his faculty as of July 2022. He is clinically based here in Oakland. I am happy to have him as a full time clinician here. Not only is he is he a great clinician but he has also invested in foreign research endeavors. His research interests are focused on improving our understanding of health disparities in pediatric rheumatic diseases particularly particularly juvenile idiopathic arthritis or J. And lupus recently published in arthritis care and research which was highlighted in this month's issue of american College of Rheumatology E. News room. He is currently funded by the Arthritis Foundation to apply epidemiological methods to study the intersectionality between race and ethnicity with social determinants of health and disease activity and severity for patients with J. This is in collaboration with the childhood arthritis and rheumatology research alliance. Also known as Kara. Today Dr Souls will be presenting on in France topic macrophage activation syndrome, calming the cytokine storm. Thanks. Alright thank you. Hello everyone too bad. I can't see your faces but um I hope you're all here and listening. Um I'm I'm excited to present on this topic which is macrophage activation syndrome or M. A. S. Which um it's it's a consult that we get quite a bit or certainly a question that we get quite a bit in rheumatology and it's definitely a mysterious topic. So I'm hoping that over the course of this talk we can put it into a clinical case um and hopefully demystify um some of the confusion around M. A. S. I have no relevant disclosures. So our objectives today are to one identify rheumatic diseases that are associated with the development of M. A. S. To to evaluate the similarities and differences between M. A. S. And secondary versus primary hemophilia acidic histiocytosis which we will just call H. L. H. For the rest of the talk and the number three to use current diagnostic work up and treatment approaches for both M. A. S. And secondary H. L. H. And just to provide a little roadmap for where we're going today we're gonna start with a case presentation. Um Then just go over some definitions clinical presentation, path of physiology um and then dive into a nomenclature review and sort of demystify this confusion between M. A. S. And H. L. H. Hopefully. Um And then talk about diagnostic work up and treatment approach and then um some concluding thoughts from a rheumatologist perspective. So first let's start with the case. Um So this is an eight year old boy who was previously healthy and admitted a purple team at summit um for about a month history of fever and rash. When we talked to mom, we learned that the fever is occurring daily and usually in the evening time generally with the ti max around 100 and one that resolves with or without anti pirate IX, which she's no longer using because it doesn't seem to make too much of a difference. Um, she doesn't use these terms, but she reports a rash over the trunk and back, which was uh in appearance from photos look like arithmetic, smack you als and we'll look at some photos in a bit. Um and really the only other pertinent part of the history is that this boy complaints also lower extremity pain, which he, you know really localizes to his entire leg. And mom notes that he's walking on his tip toes. Often there are no sick contacts or respiratory symptoms though. He did have a close household contact who was diagnosed with tuberculosis about a year ago and treated per report. Okay, so a lot of words here, but um, just briefly going over his exam and pertinent labs. So he is febrile but otherwise with reassuring labs. His exam is overall unremarkable. With the exception of some mild tenderness within version and the version of his ankles bilaterally without really clear joint swelling will come back to in a bit. And labs wise we see that he's definitely systemically inflamed with a very high rate of 75 crp of 110.8. Um Some of these labs were collected with the help of a rheumatology consult. Um But uh include a fair 10 of over 1000 and elevated diner and fibrinogen ACBC which is mostly reassuring minus enormous civic anemia. Um and then an elevated LDH to 633. Um There were many infectious studies that were done but just to highlight that he was negative initially on an E. V. V. Mono spot. So when we think about the differential diagnosis for um this eight year olds who would be classified as having a fever of unknown origin. Um You know I think from the rheumatology perspective and probably similar to many of you we think of three big buckets of disease categories one being infectious. Um The second being oncological and then of course the third being rheumatoid logic. Um I should say is a non exhaustive list of potential infectious ideologies and I didn't really touch on um any potential exposures that might guide this infectious differential. Um But some things that we consider from the rheumatologist perspective or endocarditis or acute rheumatic fever with persistent fever and rash um particularly if there was any limb pattern apathy we would think about cat scratch disease or if there is a history of exposure um brucellosis michael plasma and then also TB in this setting with a positive contact at home from the oncological perspective. We think about leukemia and lymphoma in particular. We hear about joint complaints in the history. But of course other malignancy might be on the differential. As I said this is a non exhaustive list. So hopefully I. D. And oncology art um too upset with me for the short differential. Um But getting into the rheumatology side uh this is a list of things that we would think about. So of course lupus, drama thomas, itis um systemic juvenile idiopathic arthritis or other juvenile arthritis. These um perhaps if there had been an exposure to amoxicillin or the antibiotics. We think about serum sickness uh coochie disease. Um And I won't read them all but a few other inflammatory syndromes that potentially could be on the differential for this child with fever and rash. So continued work up was done both I. D. And oncology were consulted. Um And um I think much to the chagrin of the admitting teams. We did ask for a whole body M. R. I. Because it was really unclear based off of his history whether or not there was any arthritis present but the whole body M. R. I did reveal abnormal bilateral shoulder infusions, knee joint infusions and ankle joint infusions without narrow adama surrounding the joints. And this led us to the diagnosis of systemic juvenile idiopathic arthritis. Um This is related to M. A. S. So I thought it would be worthwhile just to review some of the diagnostic criteria and some photos rose and clinical pearls about this syndrome, but this is sort of a unique form of arthritis where really arthritis must be present and can be present in any number of joints. Though I will say isn't always obvious that disease onset as we saw in this case, patients should have fever for at least two weeks in duration and that is daily or you know, the boards were the buzzword would be quotidian for at least three days of that two week period and must also be accompanied by at least one of the following. So one is evanescent rash which we heard in our history, generalized lymphatic apathy, enlargement of the spleen or liver and cirrhosis. Itis. Um Any of the LR diagnostic classification criteria, that's International League for rheumatology um requires that patients be less than 16. And so if this patient were 16 or greater we would. Um This anonymous adult counterpart is adult onset Still's disease And just um a pop culture plug. Um if anybody saw the 2017 film, the big sick um with Camila and Johnny, his wife in this movie um was ultimately diagnosed with still's disease and was kind of a mystery diagnosis. So this is a diagnosis that's often hard to capture and we'll go over some pearls of of why that might be but really quick just before we segue into that. I just want to review very briefly that j ia is a heterogeneous group of diseases. It is a catch all term but it does not refer to the same thing. Um So for example, there are other subtypes of juvenile arthritis that as a rheumatologist we wouldn't think about in this scenario because they wouldn't accompany the daily fever and rash. But just to say that there um you know when you're thinking about a juvenile arthritic E. J. I. Is not a strict diagnosis. So for example oligarchical urge ai a very briefly it tends to impact young Children, particularly toddler or school aged and is classified by having four or less joints of involvement versus poly articular J. I. A. Which especially in the rheumatoid factor positive subcategory would more closely resemble an adult rheumatoid arthritis patient. And then of course there was a smattering of psoriatic arthritis and emphasize this related arthritis which is similar to um in closing spondylitis and are on the spectrum of disease category. We call spagnolo arthropod, these affecting the axial spine. And then of course this is sort of a catch all the undifferentiated J. I. If you don't neatly fit one of the categories and of course systemic J. A. So just a few pearls over this very brief J. Review. So all J requires an age, a diagnosis of less than 16. All requires the presence of arthritis which where we are as rheumatologists are very happy to help with but just as a reminder that our three does not equal arthritis. Arthritis must include the presence of an infusion or swelling or elimination and range of motion plus pain. And with the exception of systemic J. A. All require symptoms for at least six weeks of duration. So I think we don't run into this scenario often where patients present with joint pain and it's very acute onset and obviously we're always happy to console. But it's sometimes a little hard to know because we just don't have enough time yet to say if this is gonna be, you know, an infectious or post infectious related phenomenon versus a true persistent inflammatory arthritis. So just reviewing some of the pearls of systemic JR. Again, this buzz term quotidian fever. This picture here highlights what is very typical. Um And our pearl. If you look at on apex the synopsis or fever tab, you can get a very nice graph that looks just like this. Um But what we see is one fever per day. It tends to spike in the afternoon or evening hours. Um with a cute drop as you sort of approach the morning time. And as you say, see later on in this graph. Um Sometimes there's even a relative hypothermia when the fever goes away. So this, you know, characteristic spikes. Um And and valleys is very very um clear with a quotidian fever pattern not diagnostic in and of itself of systemic J. I. A. But should definitely put that in the back of your mind as far as the differential diagnosis. So the evanescent, salmon colored rash. This is really the hardest disease feature to capture. Um as you can see here in these photos of a systemic A rash, it's kind of it's very nondescript. Um I think to some of us in rheumatology, I'm not sure that I'm there yet. But you know, some of our group can just look at a rash and know for sure that's a systemic rash. But uh it is you know arithmetic smack you als or patrols that coalesce into some of these patches or plaques. And it characteristically involves the trunk and back but can involve the limbs. Um wouldn't often involve the palms or soles of the feet. And I think that the pearl to know about this rash is that it truly is evanescent. Um It is a rash that presents with fever and disappears by the time you either treat the fever or the fever goes away. So if you have a patient with either F. U. O. Or fever without a source who is admitted. And you're thinking about systemic J. A. I would just ask you to consider putting their anti paramedics on as needed. So we can monitor for fever and win febrile then checking head to toe for rash. Um Because this can be really really hard to capture. It really helps to clinch a diagnosis when it's present. So other manifestations of the disease. The last part, you know of the name obviously is arthritis which I will say is rarely mono articular. It tends to involve the knees, the wrists and the ankles. And or can be accompanied by tino sign uveitis, which is inflammation along the tendon approximating a joint. Um But it really can involve any any joint. So if we find one joint of arthritis that counts as far as the diagnostic criteria. Um Other associated symptoms include my al Jas. We remember that cyrus itis meaning either pericarditis, pleural effusion or as cities may be present. That was part of the diagnostic criteria. Lymphatic apathy, split omega li paddle, Meagley. Uh And very rarely patients can present with cns features such as altered mental status, seizure but that is not as common. And we see in this photo this um core young boy who has many features um You know, we see very swollen knees for one. Um They've nicely drawn out for us as a legally um just to highlight a few of the features of this syndrome. So returning to our case, so we have made a diagnosis of systemic J. A. Um Actually our initial treatment approach in many Children is incest or naproxen. Um We often use naproxen because it's easier to dose. Um It's much easier to ask a child to take a medicine twice a day versus four times a day. You really need um The full schedule dozing in order to get the anti inflammatory benefit rather than just an analgesic effect. Um And this initially improved for our patients although he then had a breakthrough a fever. And what is often next hour you know go to medication are um Interleukin one blockers such as an a camera which we'll talk about later in the talk. Um Which we started at a low dose of two mg per kilogram per day. Be a nice resolution of his fever, rash and arthritis. Um And this is much text here but basically a month later he's doing very well. His labs are normal, his arthritis is gone. Um And so we are pretty feeling you know very good. Our treatment is doing what we wanted to. Um One thing just to know about anna cameras that is every day at least once a day dosing. Um And it's an injection when kids are at home. So we often then switch them to a long acting form via one in division called which is usually dosed every four weeks. And so that's what we did for our patient. Um And we would call that success. Um Two years later however so we're gonna just fast forward a little bit in time. We received a call from mom. Our patient now is three days of persistent high spiking fever. We're sending right side and neck swelling. Um You probe and he has not missed any doses of his candy kingdom Evora loris. Um no sick or he does have sick contacts. There's a brother with a viral syndrome at home. He also has some abdominal pain, nausea diarrhea four P. O. So he is sent to the O. E. D. I forgot to bold things here but he's febrile tachycardic um Otherwise normal vitals and his exam is mostly remarkable for a right sided large cervical lymph node um and a rash described as a rhythm and is confident molecules and patches. So labs are obtained and we see that he has a significantly elevated fair to no greater than 11,000 and elevated crp with the normal sedimentation rate. Um elevated A. S. T. And L. T. Um Pan side opinion a lo fi branch in without a corresponding kogel apathy and then significantly elevated D. Dimmers LDH and trans and triglycerides this time he's also found to be be be be positive. And so this leads us to a diagnosis which will review how we get there of macrophage activation syndrome or M. A. S. In a patient with systemic J. A likely secondary to acute HBV infection. So what is M. A. S. So mes is a massive systemic inflammatory response that's associated with a lot of the lab abnormalities that we saw for our patient including side up India's. A. Consumptive kogelo apathy or D. I. C. Liver dysfunction and heralded by hyper for Tunisia it's a result of excessive activation and expansion of T cells and macrophages that cause this overwhelming inflammatory reaction and we'll get in a few slides a little bit more into the details of how this happens. It is technically a form of secondary H. L. H. That is associated with dramatic disease. And it is most common of our patients found in those who have systemic J. A. Greater than those with lupus. And there are uh even less patients with Kawasaki disease who can present with M. A. S. Um Maybe we all have a little bit more experience with that now in the setting of um M. I. S. C. Where we saw more patients present with shock like features and significant hyper inflammation. Importantly M. A. S. Has a very high mortality rate if it's untreated and unrecognized it's about 20% which is quite significant. Um And just some photos here showing some sites sort of ingesting a macrophage here for example or a neutral feel rather for example. So we actually do have some classification criteria for diagnosing M. A. S. In the setting of systemic J. A. Also presented to us by ill are so in a patient who has known or suspected systemic J. A. A fair to greater than 684 and at least a thrombosis. Tenia elevated A. S. T. Elevated triglyceride level or low fight brain region. We can make a diagnosis of systemic J. A. Or sorry of M. A. S. In the setting of systemic. When we look back at our patient's labs, we see some interesting patterns. Right? And so I've highlighted in red um sort of the classification criteria he met, including significant anemia, hepatitis, high profile Britain and anemia and elevated triglyceride level. But I also wanted to highlight an interesting pattern of his inflammatory markers which show a very high crp in the setting of a low sedimentation rate. Why would that be all in patients who have um you know, a consumptive kogelo apathy and low fibrinogen sedimentation rate will be falsely low. Um And this is especially true if there's also worsening from beside a pina. So this pattern of a low set rate in the setting of a high crp particularly in a federal ill patient should raise suspicion or raise alarm for possible M. A. S. Especially if a patient has systemic gi A. That's often not true when we first meet them. Fair 10 levels also greater than 5000 specifically in a patient with systemic are concerning for M. A. S. So we will often ask for ferreting levels as a screening test and we'll talk a little bit more about that in just a minute. So clinical features of M. A. S. I mostly want to highlight that patients who present with clinical symptoms are are very late into their hyper inflammatory course. So we will often diagnose these patients based off of lab features because we're usually able to get them into care quite quickly and initiate treatment. But in the case in which a patient has unrecognized M. A. S. That's gone on uncontrolled for some time. Um These patients will look very similar to a patient with severe sepsis. So unremitting fever lymphatic legally the rash now has become a fixed rash. And it also maybe even like a hemorrhagic rash including preparation lesions rarely we can see C. N. S. Dysfunction and if that's president um findings on the CSF such as psychosis would be likely. And then of course hemo dynamic instability. Just to go back to review a little bit about the path of physiology of systemic J. A. Or M. A. S. In setting systemic J. Um let's just go through this schematic really quickly. So innate immune activation is characterized by increased inflammatory cytokine production particularly this site called I'll 18. In this setting of supreme innate immune activation, I'll 18 is able to compete and overwhelm its anti Agnes which is this ill 18 binding protein. And when this occurs there are other factors that lead to defective antigen presenting self killing which leads to uncontrolled expansion of cells such as psycho toxic T lymphocytes and NK cells said those opposite for the boxes but you know what I mean? Um And so when we have um dis regulated and overactive side of toxic T. Lymphocytes or C. D. A positive T cells along with NK cells we see um particularly pro inflammatory cytokine production but most notably interfere on gamma production and interfere on gamma production induces excessive activation of macrophages and expansion of these clones and eventually leads to macrophages with him a specific activity which further can also lead to such a toxic T. Lymphocyte activation and expansion further production of um you know this L. 18 again and other pro inflammatory cytokines here for it to make a box for it. But the end result is this leads to an uncontrolled cytokine storm. And so it's a feed forward loop. And the goal of treatment with M. A. S. Is to stop this positive cascade loop just to highlight here that for example in primary H. L. H. We have genetic mutations and performed for example this leads to aberrant NK cell activity which again then feeds again into this path of physiologic loop that we just reviewed just to highlight a little bit of how the two entities while distinct have some overlap from a path of physiology perspective. And I think that segues nicely into this confusing alphabet soup. You know, we talk about M. A. S. We talk about H. L. H. Um We talked about cytokine release syndrome that especially was a term that was used a lot during covid time. So what what does that mean? How are they different? How are they alike? Um So let's let's try to disentangle that a little bit. So with the caveat that I'm not an oncologist just to quickly review H. L. H. Also has separate diagnostic criteria. Um Where there are clinical criteria at least five of these nine must be met in order to make a diagnosis but includes similar features that we see in M. A. S. Including persistent fever, split omega li site api nias high triglycerides hyper for anemia. And then it adds in directly with testing this lower absent NK cell activity and elevated sybil. I'll too, which is another molecule that is made with excessive human specific activity. And then of course is added if there are human parasites found in the bone marrow or other pathologic areas without evidence of malignancy. Um Yet another criteria for making a diagnosis of H. L. H. Or if you have an identified mutation in a biologic um H. L. H. Associated genes such as P. R. F. One or perforation that could also make a diagnosis. So just really quick to compare H. L. H. And M. A. S. There are some key themes. So importantly there's there are similar molecular arrangements that happened including defects in the side allergic pathway. When I say that, I mean those C. D. A. Positive T cells that we saw in the prior slide and NK cell function that leads to cytokines excess particularly this I'll 18 and interferon gamma which are very important pro inflammatory cytokines in this pathway. What we also actually see are some overlap mutations of familial H. L. H jeans. As I mentioned. These are usually um you need by allele IQ or to you know, homesickness gene mutations in order to make a diagnosis. But we do see in about 35% of patients with systemic J. A. Hetero sickos variance, which suggests that there are some blurring of the lines between these two syndromes. So just some other key themes to review. So, you know, as we're alluding to here, there's no agreed upon nomenclature for H. L. H. And M. S. Related disorders. Yet their diagnosis is made by similar lab values and clinical features and many of these H. L. H. R. M. A. S really diagnoses have a common path of physiology that lead to this immune dis regulation and over activation. Now what separates the names of them are their triggers? And that's really where we see differences. What I would propose and what others in the literature have proposed is a more umbrella term to describe these syndromes called cytokine storm syndromes. And we can think of them as either primary or acquired forms of H. L. H. So of course here we have primary H. L. H. Or familial H. L. H. Like I said, associated with these gene mutations for example in preference genes which leads to this characteristic syndrome. Um and also H. L. H. Associate with other genetic disorders such as immuno deficiencies like chronic renal luminous disease. On the other arm we have acquired forms of H. L. H. Including some of the um other common triggers that we think about with H. L. H. Such as infection associated which is usually E. B. V. Rheumatoid logic associated H. L. H. Which is also known as M. A. S. Again most common and systemic versus lupus versus kawasaki disease. And then there are also malignancy associated or chemotherapy associated H. L. H. Which are acquired and therefore fallen this um side of the schematic. So I hope that this and this isn't to say that this is the end all be all way of thinking about these syndromes. But I hope it provides a framework for how we in rheumatology. Think of them as yes different but also the same. It's really the triggers that that differ and understanding if there's a genetic reason for a patient to go into H. L. H. M. S. Is very important because their treatments are very different and we'll review that in a little bit. So if if there is a patient who we suspect may have systemic J. Or M. A. S. What are some of the diagnostic work up um tests that we would recommend. So they've been on many of these slides but just to provide a list here where they're sort of enumerated in the case that's helpful. But we often get cbc screening for side of kenya's both sedimentation rate and crp and I know that um you know I'm screening for infection for example that getting both inflammatory markers may not be all that useful. Um and may not be very cost effective but for the purposes of rheumatology diagnoses we find both are helpful as there are patterns for different diseases. So all that's to say if you have rheumatology or rheumatic disease on your mind please get both cmp looking for um um lft abnormalities, baritone fibrinogen and co ags Regulus. Right? And l th now if this is a patient who has never been in M. A. S. Before or were working up for um perhaps primary or some other acquired form of H. L. H. There are a few other tests that will send I'll 18 again and the C. X. C. L. Nine which is a surrogate for interferon gamma. Those are those two very important pro inflammatory side of kinds we talked about on the path of physiology slide um significantly elevated levels of both in the right clinical context can be supportive of a diagnosis. There are also H. L. H. Labs which sometimes we defer to our human colleagues or if we're thinking about a primary form of H. L. H. Will ask for their involvement in a case. But those include tests such as NK cell activity soluble IL two receptor level city 107 A. And then of course the genetics and it may also be helpful to get an abdominal ultrasound to look for a pattern omega li and of course we're not making this decision alone but in some cases consideration of the bone marrow aspirin biopsy Just um uh interesting study about ferreting levels in the setting of pediatric illness. This is a retrospective chart review from um Texas children's. It is a little bit on the older side now I think this is from 2003 to 2005 as far as data but they retrospectively looked at every patient at texas Children's who presented at the level of greater than 500 to try to create our oc curse to understand the sensitivity and specificity for ferreting levels for a diagnosis of H. L. H. Um Along with other variables here that for example fever lt abnormalities, subpoenas etcetera importantly when they just looked at a fair level of greater than 10,000 or above alone. The sensitivity and specificity for a diagnosis of H. L. H. I should say H. L. H. M. A. S. Secondary H. L. H would have been 90 and 96% respectively. Now pretty poor positive predictive value meaning that alone isn't going to make a diagnosis in most cases. Um but also importantly had a very high negative predictive value meaning if you're ferreting level is much lower than this that was quite reassuring. So all has to say is if you can't remember that laundry list of labs getting just a ferret in level is a very good screener if you're worried about M. A. S. H. L. H. R. A cytokine release syndrome. And just the pearl here to remember is that in the pediatric population high fair to levels of greater than 10,000 maybe both sensitive and specific for these diagnoses. Now there has been further data that's come out in adult populations and is more recent. That does not suggest in adults at least that it's specific for a diagnosis. Um But food for thought and really just a plug to put in getting a fair to level if you're worried about hyper inflammation. So back to our case. So our patient was admitted started on pulse doses of steroids which is 30 mg per kilogram per dose for three days. It was also restarted on anakin ra in place of that long acting form we talked about called Solaris Arconic in a mob at a higher dose, the subsequent resolution of his rash, fever and fatigue apathy and lab abnormalities. Over the course of about two weeks in long term follow up he now remains well controlled in a higher dose of Candy Candy mob. Um And has not had any recurrence of his M. A. S. So now let's um take a dive into understanding treatment approaches for Rachel H. M. A. S. And I think the most important thing to remember is that in the case of which an underlying cause can be identified. We have to treat that underlying cause. So for example in many of our patients the systemic G. I. A. They may forget their medicine. Um They may be doing really well and you know be tired of injections for example and so not treating their underlying systemic J. Which is still present leads to the trigger of an M. A. S. Episode. More commonly however or um you know we are not able to find the exact trigger or maybe a viral ideology which doesn't have a specific treatment for example. And so we need to treat um hyper inflammation that we see and calm down the immune system and that is primarily achieved through two different types of medications. One which we've talked about is ill one blockade interleukin one or an A camera which usually starts at what we would say is the low dose of two mg per kilogram per day. But sometimes we will need to increase to as high as 10 mg per kilogram per day. But as you'll see from some literature that I'm gonna share upcoming that really is not a maximum dose and the second is corticosteroids which we think of in rheumatology as the fire hose for the fire. Um It is one of the fastest acting although most broad in its effect on the immune system and in cases of M. A. S. We also need to use post doses of steroids less commonly um treatments such as cycloSPORINE can be added as an adjunct to treatment We'll talk a little bit about treatments to come including impala mob which is anti interferon gamma and alpha which is anti I'll 18 which hopefully will um add to our armamentarium of treatment for the syndrome, especially in refractory cases. And of course if we identify that a patient does in fact have primary H. L. H. Um we don't make those decisions but they often need um dexamethasone and atop aside for the H. L. H. Protocol and possible bone marrow transplant. Um And we really rely on Rh LH and or our human colleagues to help us with treatment of primary H. L. H. So again we're coming back to the schematic just to review um places that we can block this positive feedback loop. So right here um with the production of I'll 18 interfere on Gamma I'll one that's coming from the sites which continues to drive the side of kind storm. We can use drugs like ANna camera, I'll one inhibitors. So I wanted just to review an interesting study um that highlights the benefit of anakin ra. Um And this is a study that looked at mortality in sepsis patients who are adults I should say. Um by reanalyzing a prior phase three clinical trial. So the study design of this was to determine the efficacy of anna Kimora in improving 28 day survival in sepsis with features of M. A. S. So these are patients who do not necessarily have a known diagnosis of systemic J. I. A. But they are patients presumed to have sepsis who also have features of cytokine release syndrome or M. A. S. I'm using these terms that are changeable right? It does get confusing. Um But just to drive you know we are essentially talking about the same clinical phenotype. So this was a phase three clinical trial performed at 91 centers across europe and North America where adult patients with sepsis were grouped. They either had hepatic biliary dysfunction and D. I. C. Features. This was identified as an M. A. S. Like cohort. They had one or other of those features or they had neither and that was sort of the control arm. And the intervention was treated with an A. Camera versus placebo. And actually in this study and a camera could be dosed as high as 10 mg per kilogram per hour. So we're talking very very high doses of an a camera to treat hyper inflammation. When I want to highlight here is Kaplan meier curves as far as survival probability. But we see here a significant difference. This is these two lines um highlight our mes like cohort and so their survival probability increased from 35% to 65% with the use of Anakin versus placebo which is significant and in cox proportional hazard model with you know, adjusted analysis yielded a hazard ratio of 0.28 meaning that there was a 72% reduction in mortality in those treated with Anakin ra compared to placebo if they had M. S. Like features. So I think what this is important to highlight is that a camera may have benefit in patients who have sepsis with hyper inflammation and may have some features of M. A. S. H. L. H. But don't yet quite fit the box. We can't exactly call them that yet because we don't know the underlying trigger. It can have a mortality benefit which suggests that this is safe to use in patients who we might be afraid to use an immunosuppressant in um given that we think they might have sepsis, there might be an infectious ideology driving the process. So I think this also highlights that it's not always appropriate to add an a camera and setting hyper inflammation. We wanted to make sure that there are as mirrored in this study some M. A. S. Like features such as telepathy or hepatitis um In in the scenario in which all of those criteria are present and it can really maybe a helpful adjunct in treating hyper inflammation. Um Just a few more studies to highlight that you know Anakin uses coming into vogue, so to speak in the treatment of primary or primary secondary H. L. H. Um This was a single center retrospective chart review that looked at will be a small number of only 44 patients with either secondary H. L. H. Has treated with anna Kimora and they found that patients who were treated early meaning within five days of hospitalization had a significantly a statistically significantly decreased mortality rate. Um overall the mortality rate of this court was actually quite high at 27%. And of those who were later found to have malignancy associated H. L. H. The which was only an end of three. All of those patients unfortunately passed away. Um so again highlighting that Anakin very likely has a role in treatment of piper inflammation. It may not be appropriate in all cases but certainly data to suggest that this is a helpful medication. Um And this was just an interesting study actually that looked at the use of an a Kimora. Um And in this schematic this is actually a patient who was later found out primary H. L. H. But we see here following some um markers that we follow including ferreting levels, platelet count. Um And this was in this patient's case triggered by C. M. V. That with the initiation of an a camera and a Q6-hour schedule and you know, it takes several days but eventually we see nice decline. Sharp drop off of fair 10 levels and climbing platelet count which is a very important um of all those labs that I told you about platelets or something that would monitor the most we get most worried when thrombosis Armenia is worsening. Um But in this patient at least in the short term follow up that they were able to follow anna Kimbrough was sufficient in calming the side of kind of storm. And this patient in particular ended up having malignancy associated H. L. H. So I had mentioned a couple of other treatments that were coming in the pipeline which include an anti interferon, gamma monoclonal antibody which is called M. Apollo map. Um It's not yet a medication that we're using commonly in rheumatology. Um but it is something that I think will hopefully in time become part of our practice, particularly more factory cases. Um And what's still a little bit more in the research realm right now is an anti L. T. I. L. 18 treatment called Koenig alpha. Um I think they should come up with a new name for that. Um But this is currently undergoing phase three clinical trials for the treatment of H. L. H. So just to briefly highlight that Emma polymath ab as as of now been actually studied in primary H. L. H. There was a recent 2020 new England Journal of Medicine article that summarized the results of the phase 23 clinical trial looking at 34 pediatric patients with primary H. L. H. Um and they found um this might be kind of small on your screen depending on um how big your screen is where you're watching but looking at response rates and treatment between those treated with Emma polymer which is the dark blue versus more standard treatment. There were very similar um results between both arms and so the overall conclusion was that there was similar efficacy between em Apollo mob and previously treated H. L. H. Groups which suggests that this may be a reasonable treatment for the treatment of primary H. L. H. Um Though to note serious infections were common about 30% positive is that there was no organ toxicity. As I mentioned, this was studied in the context of primary H. L. H. But there are currently clinical trials and systemic J patients currently that are ongoing and preliminary data is encouraging. So I think there is more to come for potentially Apollo mob uh politicians use in our patients. So coming from the perspective of a rheumatologist, I might suggest a paradigm shift and I don't know that this is a paradigm shift so much just as um a recognition of the nomenclature being very confusing for all of these hyper inflammation syndromes. So again as a reminder a historical framework of H. L. H. And M. A. S. Was that these were two separate clinical entities. There was primary H. L. H. Meeting H. L. H. Either clinical or diagnostic criteria associated with genetic mutations leading to perfection for example defects. Um that would cause this inflammatory cascade. And then there was the other bucket which was secondary H. L. H. Um of which M. A. S. Was a subgroup mes meaning secondary H. L. H. In the setting of a rheumatologist diagnosis but what I would propose and what I think would reflect a more modern framework of H. H. M. A. S. Is that they're these this is more of a Venn diagram. There is much overlap between these entities. Um And I even have overlap here represented between mes and primary H. L. H. Because as I mentioned we know that up to 35% of patients with systemic j. Maybe they have a heterocyclic variant for primary H. L. H. Associated genetic mutations. And so really there is a blurring between um these two diagnoses. It really more represents a clinical spectrum of disease. So there's this interesting article um from boston Children's that sort of enumerated their workflow um for concern for hyper inflammation and who calls who and how do we work this up to try to simplify um what has historically been very confusing um and very um blurry as far as um who should be driving treatment who should be driving um you know management decisions etcetera. And so I just wanted to show you this schematic and not to say that we need something exactly the same at Children's Oakland um or across the bay in san Francisco. But just to highlight that collaboration is really key in patients with hyper inflammation not otherwise specified. So in a patient for example who is thought to have possible H. L. H. M. A. S. Um on the boston side um rheumatology is consulted first um and orders are obtained per rheumatology consult which I'll show you next but they have different exit arms for involving other subspecialties. So for example if a patient did present with those rare cns features, neurology would be involved. M. R. L. P. Would be considered. For example if there were moderate to high suspicion for infection, infectious disease would be consulted and if there was moderate to high suspicion for malignancy then hematology oncology would be also consulted. So part of this room order set in their schematic includes the genetic testing which if a familiar diagnosis is confirmed the patient is then referred to oncology for further treatment. And rheumatology is involved at oncology is discretion if needed. But if there if this genetic testing is negative and there's a presumptive diagnosis of a secondary H. L. H. R. M. A. S. And meets indication for treatment rheumatology continues to follow and treats with medications like Anakin ra for example. So this is just one potential framework for thinking about this. Um But it does really highlight the collaboration and I think better mirrors that this syndrome is in fact a clinical syndrome on a spectrum. And just to show the labs that they obtain for patients with concern for H. L. H. M. S. They're very similar to all of the labs that I mentioned in the prior slide. Um But also includes like I said the genetic testing for familial H. L. H. Um And then they also had a chest X ray for potential oncological valuation. Okay so in conclusion Mes is a form of secondary H. L. H. That's associated with rheumatic disease. Again it's most common in systemic J. A. Followed by lupus and Kawasaki disease. Secondary hh exists on a clinical spectrum with primary H. L. H. With similar path of physiology clinical and laboratory features such as hyper for anemia and this umbrella or this uh group of syndromes really could be described by the umbrella term cytokine release syndromes. Treatment with an a camera is a hallmark of treatment and is associated with decreased mortality. And that was even highlighted in adult adult sepsis patients with hyper inflammation not otherwise specified. So we would suggest that you consider H. L. H. And a patient with unremitting fever and multi organ dysfunction who is not responding to conventional treatment. And as always just call us. We're here and we are very happy to help sort out inflammation as always. So it's just a if you are a lot of references if you are interested. Um And I'm happy to take any questions. Thanks for your attention. Great job Danny. Um That was a great job presenting how we approach mes and rheumatology. Um And how this really is a spectrum of disease and how we really need to work closely with our colleagues. Um And I'm glad we'll be getting more consults. Um So we do have a couple of questions. Um So far so um these questions regarding kids with Down syndrome and being that they're an increased risk for um a typical J. Which which I believe it's you know the particular JR DOWNs arthropod the um and given that they have abnormal immune systems um do do you C. H. M. S. Happening more or less rarely in kids with Down syndrome and jay? Yeah. That's a really good question. Um I would say that I personally have not seen H. H. M. A. S more common in Down syndrome patients. Um It's it's a good reminder that um as dr Leonetti was just mentioning that patients with Down syndrome are more likely to present with an inflammatory arthritis that tends to very closely resemble adult rheumatoid arthritis. Um And so it would it we tend to call it Downs associated arthropod the but it does closely sort of fit a diagnosis of poly articular J. A. Which of all the other J. Subtypes that I had talked about. Um Those thankfully are really not associated with H. H. M. A. S. It is very much the systemic J. In particular. That's not to say. And I would probably have to defer to our human colleagues if patients with Down syndrome or more likely to present with a perforation mutation for example and then therefore may be more likely to present with primary HL age but from a secondary H. M. A. S. Perspective that connection between the arthritis which is definitely there so please feel free to consult us. Um If you're worried about a patient with Down syndrome with joint pain. Um But but not likely to present with M. A. S. For that reason. Yeah. Um And then with regard to your interest in health disparities um given that most of these medications and Jr injectable, do you ever have difficulty in getting them covered for patients? Oh yes this is a good question unfortunately. Yes. So Anakin ra um the company that makes santa camera actually has a pretty wonderful patient assistance program and often we're able to get first doses of medications sent home or sent to the hospital for families prior to discharge or shortly after discharge prior to having insurance authorization. And so that generally isn't a problem. Um But often we have to submit appeals to get the camera itself and subsequent doses authorized. Um And what I find we actually have even more trouble with is authorization for Candy Kingdom at or polaris, which is the long acting form to limit injections and trauma associated with the treatment. Um It has not been studied to my knowledge yet um from a health disparities lens and it is an excellent question. Not even just for HL H. M. A. S. But for juvenile arthritis in general because many of our treatments require injection medications. Um I can say anecdotally from my experience we actually have great success getting patients who are on medic Al and I should say that systemic J. Is A Ccs associated diagnosis and C. C. S. S hardly ever gives us any trouble getting these medications approved. And so oftentimes it's actually those with private insurance who um we have the most trouble. Exactly. Um And those patients like send me sit in the hospital until we get their home does approved. So with regard to your case you presented how common are difficult in general isn't it? To obtain a whole body M. R. I. Needed or that's probably a better question for the residents. Honestly they get so upset at us. I'm sure when we ask for it. Um I think the honest answer is it depends on how busy the hospital is. Um It a little bit depends I think whether patients that summit versus main that that might not be true. That might just be my my anecdotal experience. Um But it is often delayed, its it often takes several days to get a whole body MRI if we need it. Um So we do have other tricks in our toolbox that we can use to help us get similar information which is you know in particular if there is a a specific joint that we are suspicious may have arthritis but we can't exactly tell on our exam. We might get a screening X ray for example which you know in the case of an elbow if there's an infusion there. You know it's definitely there um Or we look for bony changes such as peri articular osteopenia or erosions that might suggest to chronic arthritis. That's been there again in systemic j the arthritis isn't always the primary disease feature often starts with the hyper inflammation and later they developed the inflammatory arthritis piece. So normal X rays for sure don't rule anything out but they can be helpful. Um And every once in a while we will also try to get if it's faster and ultrasound if we're worried about this particular joint but it wouldn't be reasonable to you know ultrasound everything great. Um What is the prognosis of the patient? We presented? Good question. Um We don't have very hard data for a lot of things in rheumatology but we tend to think of patients with systemic j falling into three buckets three broad buckets. Um And about a third of patients, about a third will run into each of these three buckets. So one is patients while the mono cycle of course of disease where they present with fever, rash arthritis, it gets better with treatment we lean off of treatment and it never comes back. That's about a third of patients. Um The 2nd 3rd of patients are patients who present with polycyclic courses where they have periods of really good disease activity and then they flare and then they have good periods of disease activity and then they flare that's about a third of patients and that's likely the bucket that this patient falls in. Um And then the third are a group of patients who are just very refractory to treatment require multiple biologics develop very severe arthritis, that's very difficult to treat. Um And and again, that's about a third of patients and almost all of those patients that would definitely be a chronic course, a chronic diagnosis. And we would expect lifelong treatment. Um But in general for systemic j we try to wean off of medications about 6 to 12 months of disease remission. And there's a lot of I think um practice variability as far as you know, or experience in knowing which patients maybe are or are not going to be successful in that trial, but generally we always try. Great. I think those are only questions. Okay, great, well, thank you everyone. Just you have any questions for us. You can always consult us. We're happy to help. Created by
