Chapters Transcript Video All Who Fever Are Not Infected: Decoding Periodic Fever Syndromes Thanks everyone for joining um to talk about um periodic fever syndromes and hereditary auto-inflammatory syndromes as all that all who have fevers are not infected, so it's really important to think about other diagnoses in our clinic. I have no disclosures that pertain to this talk. I did consult for SOBI for uh patient information on macrobi ejaculation syndrome. So the objectives of this talk are to describe the differences between autoimmune and auto-inflammatory disorders. We're gonna identify key signs and symptoms concerning for an underlying auto-inflammatory syndrome. And differentiate key features between a benign pediatric fever syndrome such as PFA versus a genetic auto-inflammatory syndrome. We'll also discuss appropriate treatment approaches for these auto-inflammatory disorders. Um, so we're gonna do this by initially talking about what does the term auto-inflammatory mean, um, discussing the innate versus adaptive immune system. So going back to, um, what we learned in, uh, medical school and prior, um, we're gonna, uh, discuss inflammasomopathies, um, and go through these presentations, um, of these and other auto-inflammatory disorders. So what are auto-inflammatory disorders? So they're defined as unprovoked episodes of inflammation without high titer autoantibodies or antigen-specific T cell production. So what that means is that it's any immune system dysregulation, and they can follow um a Mendelian inheritance pattern, and um you may hear us use this interchangeably with periodic fever syndromes, um, although you may also hear us use the term auto-inflammatory disorders. So going back to um the immune system, um, we have our immune system which is that rapid response immune system which consists of these cells and our adaptive immune response which is um where B and T cells um uh combined to make uh autoantibodies and there's this overlap between T cells and uh natural killer cells. And so when we refer to autoimmune diseases, so again, different from auto-inflammatory diseases, these are diseases of the adaptive immune response. So, for example, lupus, which is our prototypical autoimmune disease, there is this anti uh antibody production to antigen or self, uh, That produces autoantibodies, um, which then combine with these antigens that lead to, um, uh, tissue damage as they deposit in tissues and, um, uh, lead to infiltration of inflammatory cells which then, uh, causes damage. So it's different from our innate immune system, um, uh, disorders, um, where again the innate immune system, it's phylogenically ancient, it's hardwired, it recognizes concerned features of pathogens, and these are not specific to a particular pathogen. It can include epithelial surfaces, phagocytosis, uh, recruitment of additional phagocy uh cytotic cells, um, as well as, um, activation of, uh, chemotractins and cytokines. It can also activate the complement cascade as the autoimmune disorders can, and again there's a link to the adaptive immune system. So going through auto-inflammatory dis uh disorders, I'm gonna focus on this paper which I recommend, um, reading, um, because this goes through the different classification of, um, auto-inflammatory disorders, um, and this really paved the way for how we think of auto-inflammatory disorders, um, where this, um, paper came out in 2009 called Horror Horror Autoinflammaticus, um, for our, from our group, um, at the NIH. And so this is a classification um uh based on molecular mechanisms and I'm gonna first uh talk about the inflammsomopathy since these are um slightly more common and what we may see uh more so in clinic. So we think of the inflammasome, so this um is in cells of the immune system, macrophages and neutrophils, um, and what um happens to eventually lead to um IL-1 beta production, which again is a pro-inflammatory cytokine which incites those of these disorders. NLRP3 um uh joins with ASC and caspase one which then leads to cleavage of pro IL-1 beta, um, and, uh, the generation of IL-1 beta which drives the processes. So these are the more common. Um, uh, inflammatoryopathies which we may see in our clinic, um, uh, the CAPS disorders, FMS, FMF, um, hyperimmunoglobulin D syndrome, and, uh, PAPA. I have an asterisk here since this, uh, doesn't present as much as a pia fever syndrome. Um, patients may have pyogenic arthritis, so, uh, neutrophilic predominance if, um, we were to test the synovial fluid, but no, um, septic arthritis, um, pyodermic renosa, and acne. Um, so I'll start with case number one. This is a 5 year old male in your clinic with periodic fevers, um, and the onset of, uh, episodes were about a year ago, so about 4 years of age. Um, episodes may last, uh, 1 to 2 days and come every 2 weeks. And they typically consist of fever, chest pain, abdominal pain, constipation, which then leads to diarrhea, uh, rash on his lower extremities. Uh, there is a past surgical history of an appendectomy, um, and a family history of similar symptoms and history of gout. So this is FMF. This is a prototypical inflammatory, uh, disease, um, and it's the most prevalent periodic fever syndrome, uh, worldwide affecting more than 10,000 people. Um, mutations are prevalent in certain, um, ethnicities, and the carrier frequency is very high, about 1 to 5 in in specific groups, and this is higher than the carrier frequency of cystic fibrosis. Um, to put it in perspective. Um, so this was a pivotal paper in 1992 that came out by Castro and his group. It took about nine years for them to find this mutation, um, linked, um, to the MEFV gene on chromosome 16, um, but this led the way to realize that, um, auto-inflammatory recurrent fever syndromes can be inherited. Um, and, uh, led the way to the discovery of all the other, uh, puric fevers that we know, um, and eventually treatment. Um, so this is an autosomal recessive disorder, um, where the mutation is in the MFE gene, um, on chromosome 16, and this codes, um, pyrin, and pyrin is mainly expressed in neutrophils, um, and it combines with the AFC complex and, um, causes IL-1 activation. Um, and, and, uh, different mutations can be tracked, uh, along the Silk Road, and, um, the thought is like why, you know, why do so many people have this mutation or are they carriers of this mutation? Um, and the thought is, is that, um, it actually protected against the plague. So, um, uh, patients with, um, with this mutation, um, did not die from Mucinia pestides, and so, um, uh, it does have protective benefits. Um, and here is pyrin, um, which, um, can, um, activate the, um, inflammosome again linking to the IL-1 activation. Um, sorry, my arrows did not translate on Google Slides, um, to PowerPoint, um, but, um, typically onset is in infancy, um, uh, and before 20 years of age, so there's pretty early onset, but you might see some teenagers present with it, um, or maybe it was misdiagnosed earlier, um, uh, flares can occur weekly, um. And up to yearly, so it's not, um, there's no regular periodicity, um, but what's key to this diagnosis is that the, um, uh, episodes are short, they're less than 72 hours, which is very different from all of our other auto-inflammatory disorders. Um, they're usually unprovoked or they may be triggered by minor stressors, and what happens is there's an inflammation of a, uh, Organ cavity lining, so there's neutrophil migration into these areas, um, and this nicely depicts that where patients mainly typically have fevers with their episodes but can, you know, have symptoms without fevers, um, and, um, they have chest pain, abdominal pain, um, arthritis, um, and, um, symptoms of asympto meningitis. Pericarditis, um, the list goes on of what can be involved, um, but again, these are typically short-lived episodes. Um, the erosyphilis-like rash, um, is, is interesting because it can have associated arthritis underlying it, so it could look like cellulitis, but it resolves quickly with episodes, so it wouldn't make sense for inflammatory arthritis. And if the, um, or, or, or cellulitis, and if the, uh, rash were to be biopsied, there are C3 deposits in small vessels. Um, to meet criteria, um, patients, uh, would need to have these several episodes, 3 or more lasting again up to 3 days, um, and any of the minor criteria. Um, about 80 mutations have been reported. Um, there's common ones, um, including the M694V which is associated with amyloidosis, E14V8, um, may come up as well, um, but it's not considered, um, pathogenic. Treatment mainly consists of colchicine. Um, so colchicine, um, it inhibits microtubules, um, by binding to tubulin and that affects, um, migration of neutrophils, um, and this helps, um, prevent acute attacks. It's taken, uh, uh, BID. There's BID dosing. This can also decrease the risk of amyloidosis. Um, side effects can include bone marrow suppression, uh, GI upset, especially with dairy and myopathy, but we typically don't see that. And um IL-1 inhibition can be used or and it can at the start of episodes, but usually patients are not on IL-1 inhibition um uh chronically or monthly. Um, so now we have a 3 year old patient in our clinic with a history of having a rash at birth. Um, the patient continues to have episodes of rash associated with fevers lasting for 24 to 48 hours. Um, episodes appear to be triggered by the cold. There's also no periodicity. There's an irregular pattern. Um, the patient has, uh, joint pain, plus or minus arthritis, and there's a strong family history of similar symptoms. So again, going back to the inflammed zone, this um uh directly targets the inflammed zone um where there's a mutation NLRP3, um, and, uh, this is part of the cryopyrin associated pyritic syndrome, so PAS disorders where there's a spectrum of disease where a mild phenotype, um, causes FCAS, uh, or familial cold auto-inflammatory syndrome, and intermediate phenotype is knuckle-wells syndrome, and the severe phenotype is nomad. Um, so this patient has FCAS. Um, so again, these are autosomal dominant mutations of NLRP3. Um, so they, um, result in a gain of function effect and they can be, um, again, de novo or there can be a family history of these mutations where there's an excessive production of IL-1 beta. Um, patients are mainly of European descent, but could affect, um, uh, others worldwide. Um, it presents typically early on, and episodes typically occur about 30 minutes to 6 hours after exposure and last up to 72 hours or a little bit longer, um, and the severity depends on the intensity of the cold exposure. Um, interestingly, the rash is this macular papular urticaria-like rash, um, and so in, uh, what's different from typical urticaria where you might, um, were to biopsy, you see it be a sinophilic infiltrate. Um, these would have a neutrophilic perivascular infiltrate, um, and, um, patients may also have fevers, fatigue, conjunctivitis, arthralgia, and amyloidosis occurs rarely in FCAS. Um, but now moving on throughout that spectrum, now you have a 5 year old in your clinic with similar symptoms, similar pattern, um, induced by the cold. Um, there's a positive family history, but this patient also has hearing loss and it's a sensoroneural hearing loss. Um, and this then, um, uh, moves along with Spectrum to Muckle-Wells syndrome, um, and these patients, um, are, um, you know, typically have flares and their, uh, disorders but can have near permanent symptoms as well, um, and triggers cannot only be induced by cold but also hunger, other sort of, uh, stressors, um. And, um, patients may also have arthropathy with joint destruction, um, and, and hearing loss can be seen up to 70% of patients. Patients may then also um have a deposition of, uh, amyloid and which then can lead to, um, renal failure. Um, and then moving along to the more severe phenotype, this is also um known as sina, um, where, um, it's, it's rare but it's seen, um, where symptoms present at birth, and there's typically in utero evidence of dysmaturity. So perinatal events are common. Patients may have, um, uh, prematurity, growth restriction. Um, they can have that urticaria-like rash at birth. There are dysmorphic features including a south back nose, frontal crossing, um, and neurological complications. So, um, they may, um, have hydrocephalus, ventriomegaly, um, they, they also have this, um, central neural hearing loss, um, and their arthropathy is, um, very, very different than what we typically see. There's metaphysical skeletal dysplasia, patellar enlargement, and growth arrest of the affected limb. Um, they may also have flares with fever, rash, conjunctivitis, meningitis, um, and, uh, sphomegaly. Uh, interestingly, amyloidosis is less common. Patients, um, but you can see, um, parts of this, um, obviously, um, these patients have, uh, pretty significant, uh, findings, um, maybe not so much with regard to the distal features early on. You can see the salad back nose here, the frontal bossing, and obviously the rash, the earth like rash. Um, so making the diagnosis again, genetic testing is available, um, and this mutation sits on the, on chromosome 14, but not all mutations are detected, and so if there's a concern, um, or it seems like the patient may fit into this, um, we may treat as go to the tree as well. Um, so treatment again, the IL-1 is, um, it is high, um, and pretty much, um, unchecked, and so, um, IL-1 inhibition is, um, the treatment of choice. Um, where anakinra is typically used, that's our daily injection. Um, Brilano is another IO1 inhibitor which we may use once weekly, um, dosing, um, which, uh, makes it better than, um, having to always dose anakinra, uh, may not work as well. Um, and can cannikinumab, um, noted here, this is our more, um, chronic, um, long-term IL-1. Inhibitor, uh, where it, um, uh, inhibits IL-1 beta, namely, and it can resist IL-1 alpha and beta, um, and, um, this is usually the background uh IL-1 inhibition that we put on, um, where patients may be on it every 2 to 8 weeks. Uh, we usually increase the frequency, uh, up to 2 weeks if needed. Um, most patients are on it about every 4 weeks. And there are adjunctive therapies like corticosteroids, colchicine, and TNF inhibitors. Um, so moving out of the CAPS disorders, um, case number 4, we now have a 5 year old female in clinic, um, with onset of fevers at 3 months of age. Um, episodes occur monthly and last 3 to 5 days. The patient has a fever, sore throat, oral ulcers, cervical adenopathy, mild abdominal pain, and a mild rash. Um, and these episodes are exacerbated by immunizations, um, or other stressors, and prednisone may or may not be helpful. So it kind of sounds like PFAPA, but prednisone isn't helpful, so it makes you think differently, um, and also the abdominal pain may not fit, um, but, but very similar to PFAPA. So when we have something like this and we question it, we typically have to get her have a fever, uh, genetic test. just to make sure we're not missing this diagnosis. Um, so this is, um, uh, related to, uh, mevalonic kinase deficiency, um, and, um, a complete deficiency of this, um, causes mevalonic aciduria, um, or a partial deficiency causes hyper hyperimmunoglobulin D syndrome which leads to these periodic fevers. So if we Think back to our cholesterol pathway, um, where there's a deficiency is here where uh mevalonic kinase, um, so that leads to elevated mevalonic, um, uh, levels, but then we do not have the, the rest of these for general, um, is really needed, um, with regard to other, um, downstream, um, cholesterol and other pathways or other molecules needed for, um. Um, signaling and, uh, cholesterol synthesis and other, um, uh, cell mechanisms. So with regard to um MVA, so again, this is complete deficiency. These patients can also have recurrent symptoms, um, but they also have um other features such as dysmorphic features of uh mental retardation, um, failure to thrive, UVIs, lusclera, ataxia, myopathy with hypotonia which can then lead to early death, um. Hyperglobulin T syndrome though is different, uh, where patients are usually well in between episodes, so again there's a partial deficiency, otherwise things are working well, um, and patients are of, um, Dutch or Northern European descent usually but can affect, uh, others worldwide, um, and generally patients present in infancy. It's key to note, one of the things we note about this is that um events can occur after immunizations, so something to consider if you get, you know, if your patient has fevers or strange symptoms after immunizations. Um, episodes can last up to 7 days, um, but maybe anywhere from 3 to 7, and the frequency is anywhere from every 2 weeks, uh, to 12 weeks. Um, and again, patients are usually well in between episodes, they're growing well and otherwise thriving. Um, so again, the top 4, listed here are similar to what you might see in PFAPA, um, but what's different is that these patients can have extreme abdominal pain, vomiting, diarrhea. They may also get a diffuse maculopathic rash. They may have petechia purple recuanous vasculitis, so that doesn't quite fit with PFAPA, and, um, they can also get symmetric polyarthritis, which again, we don't usually see arthritis with PFA. Um, so this is, um, a photo of, um, vasculated thrash. You might see, um, so lab, there can be lab abnormalities during, um, episodes. We usually don't check them because if we have the genetic mutation we're able to get it, we, we know whether or not they're kids or not, um, but they can have elevated IgG levels, although this is rare in patients that are less than 3 years of age. Um, and unfortunately they can have, or unfortunately this can also be elevated in the setting of chronic infections or acquired immunodeficiency, so it's not pathopneumonic, um, if you do have an elevated IgD level noted in the patient, um, they may also have elevated IgA levels which we obviously see in other patients that are inflamed, um, but we can also track, um, mellonic acid which may be elevated and easy tips in the urine, um, but again, that's something we typically follow. Um, so this mutation is on chromosome 12, um, and the more typical ones that we see are the B3771 and the, and, uh, the 1268. Um, and again, IO1 inhibition, so we know its role, um, uh, the melonichitis, um, activity in a role in the, uh, inflammatory, so IO1 inhibition is recommended. Some patients may do well with NSAIDs only. TNF inhibition can be used for severe arthritis, um, and then other, um, things that we may use. The thought that maybe statins can help, um, but it may actually worsen disease, um, and severe, um, involvement such as an MPA. Um, so moving on now to a different, different mechanism, so looking at protein folding disorders in the immune system and what we may more commonly see with regard to her fevers, um, We have a um 14 year old male um with onset of episodes at 2 years of age, so early on, um, and, um, these episodes last 5 to 7 days or longer, sometimes up to 14 days. So, um, uh, very different from the other pair of fevers that we see which usually 7 days is the cutoff, um. And the flares for this patient consist of fever, puffy eyes, abdominal pain, chest pain, respiratory rash, myalgia, arthralgia, arthritis, um, and there's a family history of a grandfather that, um, passed away from kidney disease, and prednisone may or may not be helpful. So this is tumor necrosis, um, factor receptor associated periodic syndrome or TRAPS, um, also known as Hibernian fever. Um, patients are usually of Irish or Scottish ancestry, but we, um, have seen it reported, uh, various ethnicities, and this is actually the second most common hereditary periodic fever. Um, so there are mutations in this, uh, TNF, um, gene, um, on, uh, chromosome 12, um, where there's more than 50 mutations that have been identified, um, and, um, this, um, single amino acid substitution. Uh, may, uh, involve cysteine residues, uh, disrupting disulfite bonds. It's also dominant. There may be reduced penetrance. You may not see it in, uh, all the family members, but also there are de novo mutations. Um, I'll just quickly go over this diagram. So, um, And the top, um, this is normal, um, TNF receptor production and shedding, um, which then binds to, um, active TNF alpha, um, then decreasing TNF alpha that is free, um, but in, um, traps there's a concern with regard to the slowing of the protein and how it's presented, and then finally, um, how can then the UTA or activation of other cytokines leading further free TNF alpha. Um So, um, these patients also have inflammation within cirosal, uh, linings, sodium eye change manifestations, and again, episodes may also last up to sometimes even 4 weeks and may for for every 5 to 6 weeks, um, and there may be triggers including minor trauma, infection, stress, or physical exertion. Um, patients may also similar to what you might see in FMF, but again, longer episodes, um, they get scrotal inflammation, diarrhea, constipation, constipation, protonitis, um, and, um, arthritis. They can also transient contractures. Um, what's different is patients, they can have these cutaneous findings, um, where they have an Area that may migrate distally along the limb that's erythematous, and they may have associated myalgias with it, um, but there's inflammation if you were to biopsy of the underlying fascia and there's not a myositis, um, and they may have other, other inner, uh, rashes like annular plaques or patches and generalized, um, surfaceous plaques. Um, so you may see something like this again, it looks like cellulitis, like migraine, maybe associated underlying, um, myalgias and, um, with the fasciitis or either image or biopsy. Um, so the initial thought was wouldn't then anti-TNFs work for these patients, um, and actually I one inhibition works better, um, and, um, mainly because, um, uh, again, the glimosomes again involved, um, uh, even with, uh, misholding of this protein, um. And, um, Remicade, which is anti-TNF, uh, medications, a monoclonal antibodies is actually thought to possibly worsen disease and that's secondary to, um, further previous issues of, um, of the, uh, antibody, um, an TNF, um, leading, leading to more active TNF, um, and colchicine does not have any effect. Um, amyloidosis is fairly common in this disorder. It occurs in about 10% of patients, and so knowing that this, uh, patient's grandfather had a renal disease, um, makes you, you know, makes us more concerned for this, um, and, uh, this typically amyloidosis seen is typically associated with a mutation in the cystine recipes. Um, so further protein folding disorders, um, so this is something that we also may, um, commonly see, um, and refer to us for ruling out PAPA. So this is a 5 year old, um, with an 8 month history of recurrent fevers, fever. Occur every 21 days. Um, episodes last for about 5 days, um, and the patient, um, typically has a diagnosis strep throat or viral infections, um, and, um, when you see them, they're, um, ill-appearing but non-toxic, um, and, um, they feel with denopathy on exam. Otherwise, um, other than mouth sores, they otherwise look OK. Um, and labs show the patient's neutropenic, um, ANC of 100, uh, with some elevated inflammatory markers. Two weeks later, you repeat the CBC and their ANC is normal. So this is secondary to furopenia. This is cyclin furopenia, um, where there's an autosomal dominant mutation in, um, a gene that coats the lean, and this is, um, a faulty neutrophil elastase that's not correctly processed. It's then triggers pedoptosis in the bone marrow, and this happens about every 21 days, um, and so, um, it's, it's, uh, pretty, um, pretty interesting to see that, um, their, um, their neutropenia occurs like. Talk wise during that time, um, and then resolves, and these patients can get pretty sick when they have neutropenia. They can have bacterial infections. Typically, um, hematology, um, either diagnoses these patients or sees these patients, um, they're usually referred more to them because they may be noticed to have, uh, neutropenia when you do get labs in the primary, uh, care setting, um, and they treat these patients with GCSF and make sure that they don't have a bacterial infection during those times. So we don't really, we don't give these patients immunosuppression. Who knows, it may be helpful. Um, so I'm briefly gonna review some other ones that um uh have been uh noted cause I think it's just very interesting. So deficiency of interleukin one receptor antagonists, uh, was noted, um, uh, fairly soon, uh, after, um, that, uh, uh, auto one of its paper came out, um, and these are patients that have, um, uh, Classic bone findings, classic rash, um, and, um, IL-1 inhibition really, um, helps them. Uh, chromosaho, so when we think of chronic recurrent multifocal osteomyelitis, if it's just kind of regular, not associated with other features, we usually treat that more with anti TNF medications, but there can be ones that are associated with um the inflammosome and the GED syndromes, one of them are Sappho, um, so patients may have uh bone edema, chromo lesions, uh, just um arthritic um anemia as well as um Uh, neutrophilic dermatosis. Um, this syndrome as well, we, it's usually seen more in adult patients, but there can be a monoclonal IgM thermopathy. Patients may present fevers from the neuralgias, um, and then even type 2 diabetes, the thought is that is there. Component that's related to the inflammosome and there was a study that looked at treating patients with IL-1, um, antagonists, um, with the kinara and they actually did, uh, better with regard to, um, glycemia, um, and improved B cell secretory function. Um, NF Kappa B activation disorders, briefly to go over them. So early onset Crohn's disease or Blouse disease, which is early onset sarcoidosis, can fit with this. These are patients that may have nod 2 mutations. When we do get cardiac fever panel testing or genetic testing, we commonly see nod 2 mutations. Not all of them are associated with these, but we do have a database to see whether or not they're more likely to be associated with early onset Crohn's or sarcoidosis, and we may monitor them closely for these. Um, and here, um, it's like it's a little blurry, even the bottom, um, photo we have a patient with, um, lab syndrome, so early onset sarcoidosis. You can see a non-pCding granuloma here on biopsy. They may have, uh, disfiguring arthritis and eye inflammation as well as flashes, um. Other protein folding disorders of the immune system, so spondyloarthropathies, they can be related to HLAB27, so there's a misfolding of that protein or haplotype. So these are patients with emis related arthritis, um, related to HLAB27 pussy, but of emisitis, and also axial skeletal involvement. Complement disorders, you didn't go over these, but these can relate to atypical HUS. Osteoarthritis is also thought to possibly be secondary to this, um, and then with regard to cytokine signaling disorders, cherubism, um, which, um, uh, can occur, um, where there's, uh, demolish, uh, the bones just Destruction and then that's filled with fibrous tissue um as well and then with regard to macrophage activation, we think of um macrophage activation syndrome, familial, uh, so primary HLH or secondary HLH and also genetic mutations associated with it. And also thought can atherosclerosis be, um, uh, maybe augmented by, um, preventing macrophage activation. Um, so now I'm gonna move into auto-inflammatory disorders of unknown etiology. So these are patients that um you may see that have fevers, um, and, um, and again not secondary to an autoimmune cause like lupus, um, and, um, before that I'm gonna go over our systemic, uh, JAA. Um, Bachette's, P bapha, and SERF, which is a newer auto-inflammatory or parent fever that um we density the acronym to. Um, so systemic J, I think it's important to note because, um, uh, these patients usually are the ones that we see for, uh, FUOs, um, and, um, so they don't really have a periodicity to their fevers, but we typically wanna see is that they do have, um, a, um, diurnal variant of their fever where, uh, uh, the same time, uh, of the day, either early morning or nighttime, they spike a very high temperature, and then, um, they usually in between. Um, these fever spikes, their temp their temperatures go fairly low. Um, and so it's a certain pattern we look for, um, and we also ask that, um, to see whether or not they have this evanescent, uh, rash which, um, seems to move, uh, move about and also worsen or come about when they have a fever as long as they're not in macro activation syndrome, because at that time, the, uh, rash, if that were to occur, would be more persistent. And they may have arthritis, a lot of times they mainly present with arthralgias. Um, and it's important with these patients because NSAIDs, um, are the initial treatment for these patients, although we obviously have better medications now, um, to, to really hold if we're questioning this, we hold all NSAIDs cause we wanna see, we don't wanna partially treat and we wanna see if we can, um, You know, see any of these patterns, um, cause that will help with diagnosis. If not, it's a diagnosis of exclusion, so we have to make sure it's not infectious etiology and blood oncologic etiology or other cause, um, for these fevers. Um, patients is interesting too. Patients can either have persistent fevers or have sort of flares, um, and episodes, and, um, their episodes may consist of, um, mouth sores, genital sores, um, like a folliculitis, um, and down on the Bottom right, I have um a photo of pathhargy um where um patients if you were to either, either they get an IV or have a um a lab draw may then initially have a vessel which then leads to sort of an um ulceration. um. Patients may also present with neuro um Bachette's and this is a photo of um a dural venous sinus, um, thrombosis, uh, where if this is seen, um, it should, you know, make us think about whether or not they have, um, Bachette's, um, because it's a vasculitis and, um, can involve, uh, thrombosis, arterial and venous thrombosis, but this is a typical, uh, area where the thrombosis is seen. Um So for the final two, I'll go over a couple of cases. Um, so case number 7, we have a 5 year old male with onset of episodes at 1 year of age, um, and they occur monthly and last 3 to 5 days. Um, the patient has a fever, sore throat, plus or mild myoscleral ulcerations, uh, cervical adenopathy. Mild abdominal pain and a mild rash, and with prednisone, there's a prompt resolution of symptoms. So this is classic for Pinkbapha. Um, it's the most common, um, uh, um, purrhact fever syndrome. Uh, it's not monogenic, meaning it's not related to one genetic mutation or one, chromosome, but we think it's somewhat familial. There's Likely some genetic, um, haplotypes or or genetic preposition to this as we get, um, a history usually that maybe the parent or the grandparent had frequent sore throats or pharyngitis or strep, and they got their tonsils out and they were better. Um, so with PAPA, when we get a history of this remarkable period of speed, like if they know, families know when the episode's gonna happen, it's like every 4 weeks for them or every 6 weeks for them, they just, they're ready for it. Um, again, episodes are usually less than 7 days or about 5 to 7, and, and most patients have the identical symptoms each time. So, um, so a patient may have lymphadenopathy, a sore throat, and, um, a little bit of stomach. Upset, although it makes us question, do we have to think about these other disorders, um, but every time it's like clockwork, they literally have the same symptoms every time. Well, you might have another patient with PAPA who might have, uh, mouth sores, lymphadenopathy, uh, as their primary symptoms and may have those symptoms every time. Um, so symptoms usually start between, uh, 2 to 5 years of age, and we tell our patients that they usually burn out by age 10 or 12. Uh, that being said, I have seen patients present later. I have teenagers coming to me, early patients in their early 20s. I have older patients, adults calling, um, that they have BAPA symptoms. Um, and, um, again, patients. may burn out by age 10 or 12. I think part of it depends on when they first present, because if they present a little bit later in age for the first episode, it seems to possibly last a little bit longer, um, and, um, what we might notice before it, uh, burns out is that episodes may become shorter in duration and less frequent. Um, so with these episodes, the fever onset is abrupt. And there's usually prodromal symptoms, remember families kind of know like, oh no, it's, it's week 4, we're about their, you know, my child's about to get their episode, but they, they can see it the day before too, they might have like more malaise or irritability or start having a sore throat or some lymphadenopathy before the fever strikes, and um that's when they, we tell them if it seems like a typical episode, it's OK to start treating. Um, so with regard to criteria, um, I'll briefly go through this. We did, you want to exclude selective neutropenia or really any other disorders, um, but again, uh, these patients are gonna be, uh, completely well between episodes and have normal growth and development. Um, so prednisone, I'll, I'll let you know about our algorithm and what we use, um, but typically, uh, 1 to 2 mg per kilo as an abortive dose at the start of what looks like a typical episode. Cemetidine can be used as a preventive medicine as well as colchicine. Tonsillectomy may be, um, something that families want, although it's not always curative and symptoms may come back a few years later. It may not be associated with fevers, but it may not be their typical episodes, um, that come. And, um, uh, and Akira can be sort of symptoms if they're very severe, um, and, uh, vitamin D is very important. And so, um, vitamin D is actually very important in all these, but we realize that vitamin D, um, it helps modulate the immune system, um, and keeping a normal level can help prevent episodes. Um, we also make sure to keep our vitamin D levels high in all of our autoimmune and auto-inflammatory disorders, um, at least greater than 30 and maybe closer to 50 is actually a better level to help modulate the immune system. Um, so this is our CA CTP, so it's our pediatric auto-inflammatory working group, and this is our consultant treatment plan that we, um, uh, uh, have rolled out, uh, where there is, you know, maybe some patients or families might want an, um, antipyretic arm where maybe they just wanna use, um, like NSAIDs, um, uh, or Tylenol to help symptoms, but symptoms are usually pretty bad as a kid gets. Older and they're pretty laid out, they usually want something else, uh, so that they can participate in school on their activities. Um, so typically, and what is diagnostic is giving a dose of, uh, corticosteroids. We initially recommend 1 per kilo of prednisone or prednisolone, maxi at 30 mg at the start of what looks like a typical febrile episode. If the fever recurs, uh, uh, by the next day, they can give another dose. And it's considered an incomplete response again if a fever recurs the next day, um, or if their fever interval if they have an episode, um, that is, uh, more frequent. So what can happen is prednisone can increase the frequency of episodes, so we warn patients of that. But then we want them to let us know that because if that's the case, then I recommend they give a 2 per kilo maximate 60 mg of prednisone at the start of an episode and that usually pushes it out. Um, some patients are pushed out like their next episodes for 3 or 6 months, it really can be really helpful. Um, or if they wanna do prophylaxis, so I had some families that are just don't wanna do steroids at all, um, and understandably it's, you know, they're worried about side effects, although we don't really get too concerned about side effects if they're only, um, taking it, you know, once or twice a month as a single dose, um. But, um, colchicine can be really helpful or cimetidine. If cimetidine, if I were to prescribe it, excuse me, um, I pushed the dose closer to 20 mg per kilo kilo per dose twice a day as I don't think the 10 really works and as the patient grows, um, increasing that dose is really important to make sure that's preventative and again, you have the surgical arm as well. Um, this I wanted to briefly mention that um it was interesting during the pandemic, I participated um in the study, um, which, uh, we have a national study looking at, um, all the increase in periodic fever, um, uh, syndrome referrals that we were, um, that were sent over to us, um, and that's because, you know, a lot of patients were locked down with their family. And they couldn't just attribute their symptoms to having like a viral illness, um, that they got from daycare or school, um, and, um, what parents were noting is that their, their, um, children were getting fevers and no one else was sick. They were tested for COVID, they were negative, and so most of them, uh, ended up having, um, uh, P sappa. Um, and interestingly, what I noticed that during that time, at least at our institution, patients wanted to go for tonsillectomy, they just did not want to deal with having to, um, get COVID tested each time, just deal with symptoms, and that would delay their, uh, ability to go back to school once he was in person. Um So now this is our final case. Um, this is an 8 year old with a 2-year history of recurrent fevers occurring every 3 to 6 weeks. Episodes last 5 to 7 days, um, also with mouth sores, occasional rash, which is non-pruritic, so full lymphadenopathy, um, also well between, uh, episodes, and there's a family history of autoimmunity. Um, we may see that again, this is an inflammatory disorder, but again, we might see some autoimmunity as well. Um, exam is unremarkable. Uh, patients had a workup with a normal cytokine panel, normal or negative infectious evaluation, uh, and BT, uh, primary immune deficiency panel shows many BSs, but no pathogenic mutations, uh, fairly good response to board prednisone. Um, patient went on to have a tonsillectomy but continues to have fevers that's shorter and less frequent. Um, so this is a newer termed, um, uh, current fever, um, called, uh, SER, um, syndrome undifferentiated recurrent fever, and, um, our San Diego colleagues, um, Italian colleagues, uh, term this, um, and these patients, um, look like PFA, but not exactly. They may have more arthralgias, abdominal pain, myalgias, um, and, um, they, um, may respond better, respond better to colchicine. Um, and possibly IL-1 inhibition in patients that are colchicine resistant, and there's a questionable response to tonsillectomies. Um, so these are patients that again didn't have a genetic mutation, so early on before we had this, this acronym for them, um, or diagnosis, um, we, you know, thought they were PFAP alike, we treated them like it, but maybe Weren't fully responsive to some of the things and again had different symptoms that we weren't really expecting people, but these symptoms would also drive us to obtain the para fever testings again, it could look like a hyper IDD syndrome which we, um, you know, may wanna treat with more chronic or long-term, I should say I one condition like a panicamab which is that that monthly injection. So, I wanna refer you over to the Nova Alliance. We are redoing this website, but it has a great comparison chart of uh systemic auto-inflammatory diseases. There's many more to add, um, and, um, some take-home points of this, I want you to think about auto-inflammatory diseases with puria symptoms that resolve on their own, plus or minus if they have chronic symptoms or inflammation in between. Um, these are on, uh, a continuous spectrum of disease, so everyone presents a little bit differently and some may be worse than others. Genetic testing again may be helpful, especially if the symptoms don't quite fit, um, and, um, we do have various treatment options, um, as well. And I wanna end my talk by um uh briefly discussing this um NAH meeting that I went to, uh, last week, and I was, uh, proud to be um a moderator of one of the talks there and also um asked to be the US Ambassador for the auto-inflammatory, uh, US sites, um, as we're trying, we have this global initiative to really, um, expand, um, knowledge of these, um, diagnoses and also treatment cause there's many countries that don't even have medications like such as island ambition, um, or, uh, uh, any of the medications we have really. And, um, this was really to honor, uh, Daniel Castner, um, who, again, he's the one who developed, um, really this. And he, he, um, is the one who, uh, first noted the MAB gene mutations, I know these are monogenic disorders, um, and from that came all the other discoveries of all the other genetic mutations and mono uh genetic uh auto-inflammatory disorders and, and non-monogenic ones, um. And he really shaped um this um field, um, and has really helped, um, uh, you know, pioneer work for other people who are interested in this and um really has helped all of our patients. Um, so we're very, uh, grateful for him and it was a really great international meeting, um, which I was happy to be a part of. Great, I know there's a lot of information that I got through fairly quickly, um, and there's so many more I could, uh, talk about, um, that I wanted to make sure we had time for questions. Created by
