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Episode 27: VEXAS syndrome · Medicine Matters: The Springer Medicine Podcast

• 0:11
  Speaker 0: Hello
• 0:11
  Speaker 2: and welcome to Medicine Matters, the springer medicine podcast.
• 0:16
  Speaker 2: I'm Dr Natalie Wood – i can't wait for you.
• 0:19
  Speaker 2: listen this episode which tells fascinating stories so far of Vexus syndrome an auto inflammatory disorder that was only discovered in twenty-twenty.
• 0:30
  Speaker 2: Despite such a short amount time passing since first patients were identified A vast amount has been learned about life threatening condition.
• 0:38
  Speaker 2: Not only is it reshaping how we think about inflammatory diseases, It's also driving a truly multidisciplinary approach to research diagnosis and care.
• 0:47
  Speaker 2: Bridging as it does rheumatology immunology hematology dermatology and genetics.
• 0:56
  Speaker 2: So without further ado I invite you to sit back and listen As Dr Peter Grayson shares his many insights into Vexa syndrome as well as his hopes for the future.
• 1:07
  Speaker 2: Enjoy
• 1:08
  Speaker 1: Hello, I'm Shreya Nanda a Senior Clinical Content Manager at Springer Medicine focusing on rheumatology and oncology.
• 1:15
  Speaker 1: Today we're going to be talking about Vexus Syndrome And in addition our expert guest will also be delighted to join by my co-host who i'll now hand over so she can introduce herself.
• 1:26
  Speaker 3: Hi Shreha thanks for having me.
• 1:28
  Speaker 3: My name is Sarah Onora the Chief Editor of The Journal Nature Reviews Rheumatogy.
• 1:33
  Speaker 1: So Sarah, before you introduce our guest I have a quick question for you because when i proposed this episode.
• 1:39
  Speaker 1: I suggested a few topics but This was the one that you were most keen on.
• 1:42
  Speaker 1: so can You tell us why?
• 1:45
  Speaker 3: Well we've covered vexus syndrome in nature reviews rheumatology since The first reports came out In twenty-twenty and the story is fascinating!You got the discovery of A completely new type Of disease That Was basically hiding in plain sight And the research around VEXIS has led to new ways of thinking about auto-inflammatory diseases and somatic mutations within just a few years.
• 2:03
  Speaker 3: We're delighted to have with us Dr Peter Grayson from The National Institutes Of Health in the USA, welcome Peter!
• 2:09
  Speaker 0: Thanks for having me.
• 2:11
  Speaker 3: So we've mentioned Vexis Syndrome was first identified only a few
• 2:20
  Speaker 0: Sure.
• 2:20
  Speaker 0: So this disease was initially discovered at the intramural research program of The National Institutes Of Health, which is a program in Bethesda, Maryland where we do kind-of high risk hybrid ward clinical translational basic research.
• 2:34
  Speaker 0: and Really?
• 2:34
  Speaker 0: This story I think came about in two different directions.
• 2:37
  Speaker 0: one Was A Clinical Direction And One Was A Genetic Direction.
• 2:41
  Speaker 0: From The Clinical Side We Initially Identified These Patients from Three Main Cohorts.
• 2:47
  Speaker 0: One of them was this undiagnosed disease program, which started at the NIH and is now in network centers around the United States.
• 2:54
  Speaker 0: This program allows physicians and patients themselves to be referred into intramural programs for evaluation.
• 3:01
  Speaker 0: Often we see patients who don't fit a textbook that you can't classify their diseases there's no firm diagnosis And it really a cohort thats ripe for disease discovery.
• 3:11
  Speaker 0: The other cohort Dan Kastner fever clinic specializes in patients with auto-inflammatory syndromes.
• 3:18
  Speaker 0: These are often pediatric patients, diseases that occur genetically early in life.
• 3:23
  Speaker 0: but he also sees adult onset patients.
• 3:25
  Speaker 0: and then the third cohort was my cohort And so I've been at the NIH for over ten years started a translational research program in vasculitis.
• 3:33
  Speaker 0: So we see patients all different forms of Vasculitis.
• 3:37
  Speaker 0: as it's happened We had interest in disease called relapsing polychondritis which is a disease of cartilage inflammation as well as many different forms of aculitis, and that is the clinical features these patients with VEXes have.
• 3:49
  Speaker 0: From the genetic side of things though it's where this story gets really interesting because These patients come through the NIH And we often get exome sequencing.
• 3:59
  Speaker 0: so we sequence their DNA.
• 4:01
  Speaker 0: Those go into databases that were used to discover diseases look for novel Genetic variants in association specific clinical phenotypes.
• 4:11
  Speaker 0: But what happened in the VEXA story is there was a fellow named David Beck who's working at Dan Kastner's lab and he had pretty radical idea about disease discovery which we've called genotype first approach.
• 4:23
  Speaker 0: What that meant, it went into those genetic databases applied filtering algorithms to try identify patients with shared genetic variants not described any healthy human population database from this.
• 4:38
  Speaker 0: exercise found that ended up having what we now know as VEXA syndrome.
• 4:43
  Speaker 0: And he did this not by looking at their clinical features, not by the medical records just purely analyzing genetic data.
• 4:50
  Speaker 0: and when those three patients popped out they all had a missense mutation in the gene called UBA-I then went back to chart and started realizing oh these are patients who have been seen in Peter Grayson's clinic and Dan Kastner's clinic.
• 5:05
  Speaker 3: These patients who you discovered all had the same underlying mutation.
• 5:08
  Speaker 3: Did they all have similar clinical features?
• 5:11
  Speaker 0: They all had two major features, which is what made them stand out to us originally in that they had very difficult-to control inflammation throughout the body but in specific locations as well.
• 5:22
  Speaker 0: and that was combined with progressive bone marrow failure.
• 5:26
  Speaker 0: And clinically we were really struggling between rheumatology and hematology.
• 5:34
  Speaker 0: because from the rheumatology side, you know they had bad inflammation and it was difficult to control with any other drug besides glucocorticoids.
• 5:42
  Speaker 0: But we couldn't explain why they were getting progressive cytopenia while their marrow was failing.
• 5:47
  Speaker 0: so we were going to our hematology oncology colleagues in saying what's happening in the marrow?
• 5:52
  Speaker 0: And they were saying to us well we've looked at the marrow there is nothing clearly that we recognize And back and forth we went, the patients went back-and-forth between our two disciplines until We sort of unlocked to the insight that kind of linked everything together.
• 6:13
  Speaker 3: Can you tell us a bit more about The Key Clinical Manifestations?
• 6:17
  Speaker 0: Yeah it's an interesting phenotype.
• 6:18
  Speaker 0: so maybe I'll take A step back and just Tell You what the key clinical symptoms are because It's actually very easy diagnosis To make and to recognize when you know What your looking for.
• 6:28
  Speaker 0: So they have a lot of different symptoms throughout their body.
• 6:32
  Speaker 0: A lot of difference.
• 6:33
  Speaker 0: organs can be involved, but there's few that are really key and That is the skin?
• 6:39
  Speaker 0: The eyes...the cartilage.. the lungs....and blood vessels.
• 6:43
  Speaker 0: So these patients will get recurrent skin infections And it's wide spectrum things But often Neutrophilic Dermatosis so sweet syndrome and they'll get Urticario-like lesions and vasculitis either small or medium vessels.
• 6:58
  Speaker 0: And they get ear and nose chondritis.
• 7:00
  Speaker 0: That's why they kind of look like relapsing polychondritis, They get inflammatory eye disease and they get this unusual peri orbital inflammatory swelling?
• 7:09
  Speaker 0: Then they can also get ground glass infiltrates in their lungs which turns out to be a sterile neutrophil alveolitis.
• 7:16
  Speaker 0: It looks potentially like pneumonia but isn't as well that gets oxidative pleural effusions.
• 7:21
  Speaker 0: So if you see this combination of recurrent skin, eye lungs blood vessel cartilage inflammation.
• 7:28
  Speaker 0: You think about Vexus but the real clinical tell is it's a disease of older men and It's important to understand the genetics of disease To understand why?
• 7:37
  Speaker 0: This is a disease almost exclusively in older male populations.
• 7:41
  Speaker 0: And what's going on in this disease?
• 7:43
  Speaker 0: What so unusual that its a somatic mutation.
• 7:46
  Speaker 0: Its an acquired mutation thats happening later.
• 7:50
  Speaker 0: So unlike a lot of Dan Kastner's pediatric onset diseases, these are auto-inflammatory diseases where children were born with inborn errors of immunity.
• 7:58
  Speaker 0: They inherit a mutation from their parents and the disease expresses early on life.
• 8:04
  Speaker 0: In Vexus this is a mutation that occurs only in your bone marrow not any other cell or body.
• 8:11
  Speaker 0: but it occurs sometime later when you're an adult And explains why the disease presents late and why the disease wouldn't really run in families, it's not heritable.
• 8:21
  Speaker 0: But the diseases exclusively to men because of the gene that is mutant in Vexus which is UBA-I on the X chromosome.
• 8:29
  Speaker 0: so if you're female with two X chromosomes then acquire this mutation protected by your second one.
• 8:34
  Speaker 0: but for males who have one X chromosome they are likely get this disease we've seen almost a hundred percent penetrant.
• 8:43
  Speaker 0: So putting all that together, you know an older man who's got recurrent inflammation in the skin.
• 8:51
  Speaker 0: The cartilage ,the eyes .The lungs.
• 8:54
  Speaker 0: That is a patient really should think about vexus.
• 8:56
  Speaker 0: and if they've progressive bone marrow failure or cytopenia then it becomes way more likely.
• 9:02
  Speaker 0: this is right diagnosis In terms of progression and severity.
• 9:06
  Speaker 0: like any other complex inflammatory disease we do see some milder cases when life threatening serious case.
• 9:12
  Speaker 0: On balance, it's one of the more severe life-threatening diseases that rheumatologists would take care.
• 9:17
  Speaker 0: The mortality rate for this disease is roughly fifty percent mortality by ten years after symptom onset.
• 9:23
  Speaker 0: so a lot of patients will die from this condition.
• 9:26
  Speaker 0: but the goal is to get better at managing and discover better treatments.
• 9:31
  Speaker 0: I think thats already happening just with naming the disease and recognizing standard of care starting.
• 9:40
  Speaker 1: Clearly, the disease has quite a diverse phenotype.
• 9:42
  Speaker 1: So I'm wondering can the UBA-I mutation genotype tell you anything about how the disease will manifest?
• 9:49
  Speaker 1: Would it maybe give you a clue about how it might progress in a particular patient?
• 9:54
  Speaker 0: Well we have an early insight into that.
• 9:57
  Speaker 0: It's quite interesting.
• 9:58
  Speaker 0: so The majority of patients who've been diagnosed genetically with Vexus Have mutations That cluster In one hot spot Of the uba-i gene codon-forty one.
• 10:10
  Speaker 0: And what happens is you get an amino acid substitution, there's usually a methionine amino acid at that codon and you substitute for one of three different amino acids valine elucine or threonine .And so often we will refer to these patients as having the valine variant ,the leucine variant, the threonin variant...and depending on which variant the patient has ...there is prognostic value!
• 10:31
  Speaker 0: So the patients with the valene variant have the most severe disease.
• 10:35
  Speaker 0: They tend to have the most inflammation, fevers—the fastest progressive bone marrow failure.
• 10:39
  Speaker 0: And they die the earliest.
• 10:41
  Speaker 0: and in our initial cohort no patient with a valine variant has survived longer than twelve years from symptom onset.
• 10:47
  Speaker 0: so these are patients we know up front that need be more aggressive on how you think about management.
• 10:52
  Speaker 0: The leucine variant is better prognosis But better prognosis meaning that there's less mortality in the first five years, but then you will start to see mortality even with that disease.
• 11:01
  Speaker 0: And these are patients with predominant skin diseases a lot of sweet syndrome and The three.
• 11:05
  Speaker 0: an invariant is the most common variant in vexus.
• 11:08
  Speaker 0: often These are the older men with relapsing polychondritis type phenotype and they have An intermediate prognoses.
• 11:15
  Speaker 0: but where it gets more interesting Is that?
• 11:17
  Speaker 0: You know we recognize vexis in this clinical way and most of these patients Have one of these three variants.
• 11:22
  Speaker 0: But genetic testing is now widespread available, and people are ordering it in all sorts of indications.
• 11:28
  Speaker 0: Sometimes maybe... It wasn't even something we would have recommended or thought about.
• 11:31
  Speaker 0: And then its returning new variants In different parts of the UBA-I gene.
• 11:36
  Speaker 0: As that's happening We're starting to see expansion Of the phenotype & different prognosis & different symptoms.
• 11:43
  Speaker 0: A lot has looked like more hematologic features & less inflammation And that makes sense to us because there was selection bias in the initial patients we discovered.
• 11:54
  Speaker 0: They were coming into these inflammation clinics and now, in hematology, they're kind of seeing a bigger spectrum of this condition with different mutations on different parts of the gene.
• 12:05
  Speaker 0: I think it will continue to evolve over time when you see more aspects of disease.
• 12:11
  Speaker 0: One big area is whether diseases have manifestations for females or not.
• 12:16
  Speaker 0: And that's a question I've really left unanswered at this point.
• 12:20
  Speaker 1: Thank you, That is very clear and clearly.
• 12:22
  Speaker 1: lots to unravel still with my next question.
• 12:25
  Speaker 1: You have already addressed it to certain degree but i'm going ask anyway just so you can spell out for our listeners Given the genetic basis of condition when should doctors consider testing?
• 12:37
  Speaker 0: So we think its clinical diagnosis in sense that you must be genetically confirmed.
• 12:45
  Speaker 0: What's amazing to me as a rheumatologist is we make our diagnoses often by just pattern recognition.
• 12:52
  Speaker 0: And that requires a lot of experience, particularly for these complex diseases.
• 12:56
  Speaker 0: and now we have molecular diagnostics in the Rheumatology Clinic.
• 13:01
  Speaker 0: this disease was discovered about five years ago.
• 13:03
  Speaker 0: Now it's very easy in United States To get genetic testing through a number of different commercial companies.
• 13:11
  Speaker 0: You can have results back within one week or two.
• 13:13
  Speaker 0: So if you think about it, this is a send-out blood test or marrow test.
• 13:18
  Speaker 0: And you can get these results back which I think is transformative to rheumatology.
• 13:23
  Speaker 0: but there's a big growth curve there of rheumatologists having to learn how to both think about sending genetic tests and then the challenges in pitfalls potentially interpreting them.
• 13:33
  Speaker 0: But because its so easy now to get this test i think that If disease occurs to your differential and its plausible You should test for.
• 13:42
  Speaker 0: And I think, you know it's hard to be a bit dogmatic about these are the patients who have to test.
• 13:47
  Speaker 0: These are patients that shouldn't because we keep learning this disease has expansion of phenotype.
• 13:52
  Speaker 0: but i can say if an older male patient with scan cartilage long inflammation and particularly they had certain findings on their complete blood count should test so cbc in his disease is very characteristic things.
• 14:06
  Speaker 0: at your look for macrocytosis thats one early most sensitive hematologic signs.
• 14:12
  Speaker 0: So they get an elevated MCV, often over a hundred.
• 14:15
  Speaker 0: Not every patient will have this in the initial couple years of disease but it is a pretty good clue.
• 14:20
  Speaker 0: They get progressive anemia so its macrosidic anemia and they'll get progressive thrombocytopenia.
• 14:25
  Speaker 0: And if you look at white blood cell count there's specific pattern.
• 14:29
  Speaker 0: Often their neutrophils are preserved But their monocytes become low.
• 14:33
  Speaker 0: Their lymphocytes became low Their NK cells were low.
• 14:36
  Speaker 0: If see any that kind of pattern You should test for these diseases.
• 14:40
  Speaker 1: That's an excellent summary that I'm sure our listeners will really appreciate.
• 14:44
  Speaker 1: And so as a more theoretical question, do you see a role for wider screening?
• 14:49
  Speaker 1: For this syndrome...I mean not quite population level but wider testing than just at the individual level maybe.
• 14:56
  Speaker 0: Well we do have population genetic data on this and that is where things are getting interesting when talking about sex specific differences in this.
• 15:03
  Speaker 0: A couple of groups looked up population genetic data to determine the prevalence.
• 15:10
  Speaker 0: And so, for starters the prevalence is quite high.
• 15:14
  Speaker 0: From the initial estimates that we did in the Geisinger healthcare system The prevalence was thought to be around one and fourteen thousand people Which means it's probably second most common form of vasculitis.
• 15:27
  Speaker 0: if you consider vexus avasculitis In adults beyond giant cell literatis It's more common than diseases like ALS More common then any of myelodysplastic syndrome combined.
• 15:37
  Speaker 0: And if you enrich down to the target population of people that get this disease, so men older than fifty it's one in four thousand.
• 15:44
  Speaker 0: That means there is more then a million people on the world with Vexus and clearly we haven't diagnosed that many.
• 15:50
  Speaker 0: So were missing It!
• 15:52
  Speaker 0: The other thing that the Population Genetics teaches us Is We See More Female Cases With Pathogenic UBA-I Mutations Than We Would Expect Clinically... ...and we don't yet know what these patients look like clinically because when you look at the data, they're often female patients that have lower clone burden in blood.
• 16:11
  Speaker 0: So less mutation in their blood than their male counterparts and when... The challenge has been we haven't been able to directly clinically evaluate them but if you look a chart review or this sort of low level data that we have access too They don't appear to have obvious vexes.
• 16:27
  Speaker 0: There have been case reports of Vexus in women who are caretifically normal, XX.
• 16:32
  Speaker 0: Or in women that have a chromosome or abnormality XO, Turner syndrome and monosomia of the X. those patients look exactly like their male counterparts.
• 16:40
  Speaker 0: but is there a subset of female patient with lower clonal burden?
• 16:43
  Speaker 0: That has some subtle or less characteristic features within the spectrum of VEXUS.
• 16:49
  Speaker 0: we don't know about.
• 16:50
  Speaker 0: But this disease is really everywhere.
• 16:52
  Speaker 0: And the thing that makes it, I think quite remarkable for a newly discovered disease at the NIH.
• 16:56
  Speaker 0: you know most physicians think i'm never going to see This.
• 16:59
  Speaker 0: there's probably twenty of these cases in The world.
• 17:01
  Speaker 0: That Is not true For vexes.
• 17:03
  Speaker 0: every single time any Of us on the vexus team goes and gives medical grand rounds There's always A light bulb Going off into physician's head that oh i have one of These patients and thats been Really gratifying.
• 17:14
  Speaker 0: but It also is daunting because we have to get the word out.
• 17:17
  Speaker 0: We've done a good job in rheumatology and hematology, but need do better job in dermatology who are often first physicians that see these patients because it often starts into skin.
• 17:27
  Speaker 0: But were seeing better medical awareness than our cohort at NIH of referrals in patient being diagnosed faster or seeing disease earlier stages as clonal disease progressive over time.
• 17:40
  Speaker 0: It's highly likely that intervention early really does matter in this disease.
• 17:44
  Speaker 0: it is not your usual relapsing, remitting rheumatologic disease where you're looking for the right drug... ...it probably a disease when you've got to catch it earlier and have more success therapeutically if you start interventions earlier.
• 17:57
  Speaker 3: That leads nicely into our next question Can you tell us about the management of vexacentrum?
• 18:02
  Speaker 0: So for a couple years when we're given talks about this, We would talk about the exciting pathophysiology and how conceptual This disease was.
• 18:09
  Speaker 0: And you know all of these things?
• 18:28
  Speaker 0: From the treatment and way to think about this disease is there's three ways to manage it.
• 18:33
  Speaker 0: So one would be controlling inflammation part of that disease, And two will be getting rid of mutation.
• 18:40
  Speaker 0: so you know eradication of the clone... ...and then third was all general practice specific to the disease.
• 18:47
  Speaker 0: so prophylactic strategies.
• 18:50
  Speaker 0: Most of the initial treatment efforts focused on the inflammation because that's a very obvious part Of the disease.
• 18:54
  Speaker 0: these patients will have C reactive protein levels in hundreds and they will be quite inflamed.
• 19:00
  Speaker 0: And we learned originally that the only thing that was working with steroids, and Patients would have very specific steroid thresholds.
• 19:08
  Speaker 0: You know We could have a patient on twenty milligrams of prednisone.
• 19:10
  Speaker 0: They're great.
• 19:11
  Speaker 0: you go to seventeen point five milligrams a day and they flare.
• 19:15
  Speaker 0: And so we really did need to find steroid-sparing therapies because long term use of steroids are associated with all these problems, particularly in older populations.
• 19:24
  Speaker 0: If you look at the data on our Vexus cohort... The average steroid dose for a typical patient is between fifteen to thirty milligrams of prednisone per day— just a lot!
• 19:35
  Speaker 0: We cannot get them lower than that.
• 19:37
  Speaker 0: So we need other therapies.
• 19:39
  Speaker 0: and because this is a disease, the mutation starts in your bone marrow.
• 19:42
  Speaker 0: It clonally expands through your myeloid cells to your neutrophils and monocytes.
• 19:47
  Speaker 0: so it's a disease of innate immunity And that's the way to think about.
• 19:51
  Speaker 0: you would treat.
• 19:52
  Speaker 0: You know inflammation aspects have been made immune systems.
• 19:54
  Speaker 0: often those are cytokines like interleukin one interleukan six And so not surprisingly, the main approaches for steroids bearing therapy are things like interleukin-six inhibitors, interleukan one inhibitors.
• 20:07
  Speaker 0: Jack inhibitors which inhibit a lot of different innate cytokines and we found that those drugs make patients feel better.
• 20:13
  Speaker 0: they keep them out at hospital but do not allow significant reduction in their steroid requirements.
• 20:20
  Speaker 0: They don't touch the clone.
• 20:21
  Speaker 0: The clone continues to progress.
• 20:23
  Speaker 0: So bone marrow failure or trajectory you know, cytopenia can marches on despite use of these meds.
• 20:29
  Speaker 0: So that was real perplexing for rheumatologists.
• 20:31
  Speaker 0: we're very used to these anti-cytokine therapies working great and getting patients completely off steroids and remission has become our expectation for so many rheumatologic diseases.
• 20:41
  Speaker 0: not the case here!
• 20:42
  Speaker 0: And the biggest mistakes in vexus management is rheumetologist or other physicians tapering their steroids too quickly thinking that if they start one of these drugs are going get them off steroids...and it just doesn't work.
• 20:52
  Speaker 0: So there is a role for anti-inflammatory therapies, but it's not durable enough.
• 20:56
  Speaker 0: It's not the medicines we
• 20:57
  Speaker 0: need.".
• 20:58
  Speaker 0: The bigger breakthrough has come very recently with the repurposing of hypomethyliding agents drugs like azocytidine which are used to treat myelodysplastic syndromes and in some ways vexus is within a spectrum of amylodys plastic syndrome.
• 21:13
  Speaker 0: And what got us very excited?
• 21:16
  Speaker 0: In subsets of patients who receive these agents, we reduce the amount of mutation in their blood and bone marrow.
• 21:22
  Speaker 0: And then many patients after about a year therapy those mutations become undetectable on blood and marrow.
• 21:28
  Speaker 0: When that happens... These are patients where you can get to lower doses or even get off steroids.
• 21:34
  Speaker 0: The patient feels better.
• 21:35
  Speaker 0: So I think this is big breakthrough being explored but conceptually what it tells us?
• 21:40
  Speaker 0: We find medical therapies that are cytotoxic.
• 21:44
  Speaker 0: That's what medical therapy of the future will look like in Vexus.
• 21:48
  Speaker 0: And can we find more and more specific precise therapies to do that?
• 21:52
  Speaker 0: The other aspect is prophylaxis, so these patients are profoundly susceptible to atypical and opportunistic infections.
• 21:58
  Speaker 0: PJP pneumonia, nontuberculosis mycopacterial infections... ...and when they get these infections, they die!
• 22:04
  Speaker 0: The number needed to treat-to prevent death from PJP pneumonias around four or five patients.
• 22:09
  Speaker 0: So every patient gets prophylexis for that.
• 22:12
  Speaker 0: Every patient.
• 22:12
  Speaker 0: we consider prophylaxis for alpha herpes viruses, they get a lot of recurrent soster and all these other complications.
• 22:19
  Speaker 0: And then sometimes we think about antifungal prophylexes.
• 22:22
  Speaker 0: so that's very important!
• 22:23
  Speaker 0: Then there is big clotting signal in the disease.
• 22:25
  Speaker 0: Forty-fifty percent of patients will have thromboembolic diseases or arterial or venous clots.
• 22:30
  Speaker 0: it clots more than bachettes which are in rheumatology our clotting disease or clotting inflammatory disease.
• 22:36
  Speaker 0: So thinking about anti coagulation strategies this really important.
• 22:40
  Speaker 0: but We've also gone from discovery of a disease to cure in less than a couple years.
• 22:45
  Speaker 0: because you can cure these patients and the way you cure them is with allogeneic hematopoietic stem cell transplantation.
• 22:51
  Speaker 0: Because this is a mutation that arises in bone marrow, it's only restricted to blood.
• 22:56
  Speaker 0: if you do a bone marrow transplant on those patients then you will be able to cure them.
• 23:00
  Speaker 0: The challenge there... There are many complications for transplant.
• 23:04
  Speaker 0: mortality rates are high in transplants and morbidity from graft versus host diseases infections.
• 23:10
  Speaker 0: And the patient has to be healthy enough to do this.
• 23:12
  Speaker 0: We're talking about a population of men who are on average in their late sixties, have been on steroids for awhile and had a lot of comorbidities.
• 23:20
  Speaker 0: so selection appropriate candidates were.
• 23:23
  Speaker 0: transplant is challenging but it's an option as we see younger patients these ones trying get to transplant somewhat expeditiously that I think ten thousand foot view Vexus treatment thing, but it's amazing to be able talk about some of this stuff because just a couple years ago we really only had steroids.
• 23:46
  Speaker 3: Are you at the point in having standardized treatment protocols or clinical recommendations?
• 23:50
  Speaker 0: So there are... Some of our first randomized control trials have started happening now A group of us internationally got together and we've two Vexis workshops The one in Paris-France The second one is New York City And third coming up on September in Milan Italy.
• 24:07
  Speaker 0: And from the first workshop, we actually wanted to create some sort of guideline document and so we drafted position statements.
• 24:16
  Speaker 0: We sent that to The American College Of Rheumatology.
• 24:18
  Speaker 0: they provided endorsement.
• 24:19
  Speaker 0: those were just published this year.
• 24:21
  Speaker 0: They're not exactly guidelines because quality evidence isn't there yet but guidance documents.
• 24:26
  Speaker 0: I would refer people.
• 24:28
  Speaker 0: it's a really useful document.
• 24:30
  Speaker 0: start learning about disease figure out where things know versus don't And there's really a strong international community of people that are interested in this disease, and so things are moving quite quickly which is amazing to see.
• 24:44
  Speaker 0: The other aspect about it thats great its multidisciplinary.
• 24:47
  Speaker 0: I mean this disease by nature crosses medical disciplines.
• 24:51
  Speaker 0: It doesn't respect those boundaries.
• 24:54
  Speaker 0: So we have to have rheumatologists working with immunologists Working with hematologists, working with dermatologists , working with geneticists.
• 25:03
  Speaker 0: It illustrates, this is a disease that was kind of hiding in plain sight.
• 25:06
  Speaker 0: And the reason why we missed it because it was spread out across all these medical disciplines.
• 25:11
  Speaker 0: so really does create new framework for us to start think about research across disciplines and be able speak same languages which has taken little bit time only serves patients better not bouncing back-and forth between Medical disciplines and those disciplines are unsure, you know who owns the disease.
• 25:31
  Speaker 0: I think this is a disease that really crosses out And because of that we've proposed to term for vexus as a prototype form of disease called hamato inflammatory diseases.
• 25:40
  Speaker 0: So you have autoimmune?
• 25:42
  Speaker 0: Diseases.
• 25:42
  Speaker 0: and then The great Dan Kastner coined the term auto-inflammatory diseases and we think that this is how matter.
• 25:48
  Speaker 0: inflammatory disease A disease caused by genetic mosaicism in blood so acquired mutations in blood that can produce systemic inflammation, and over time it can evolve into hematologic malignancies like myelodysplastic syndromes, myeloproliferate syndroms or lymphoperliferative syndrome.
• 26:05
  Speaker 0: And we think there will be more diseases discovered in this vein.
• 26:09
  Speaker 1: Brilliant!
• 26:09
  Speaker 1: So you've obviously talked about quite a lot of advances that have already happened in very short times.
• 26:16
  Speaker 1: but still just looking to the future what are other promising areas You know, I'm just thinking for example gene therapy or CAR T cell therapy.
• 26:26
  Speaker 1: Would any of those be things that would be researched?
• 26:31
  Speaker 0: I think their possibility is.
• 26:32
  Speaker 0: Gene Therapy would be more promising and for this disease than CAR T therapy because This is often from most patients a point mutation in the single amino acid.
• 26:40
  Speaker 0: So it's a lot like sickle cell disease where gene therapy has been very promising The pathway to get there as long And so It Is A potential option.
• 26:50
  Speaker 0: CAR T Therapy much More difficult Because We don't have a surface antigen that would be targeted on these cells.
• 26:57
  Speaker 0: And if you actually think about the burden of disease, If you take out a patient's blood and you sequence it You will find no mutation in their T-cells or B-cell because But if you look at their myeloid cells, they're neutrophils.
• 27:19
  Speaker 0: Their monocytes up to eighty percent.
• 27:21
  Speaker 0: ninety percent of the cells will carry this mutation.
• 27:24
  Speaker 0: so trying to do sophisticated approaches like CAR-T it's challenging because we really have to almost be myeloblative in this.
• 27:32
  Speaker 0: but I think that promise is as i mentioned idea that we have cytotoxic therapies could get rid off the clone medically probably its future.
• 27:41
  Speaker 0: and when you think about conceptually where we've come in rheumatology as a rheumatoidist, you know We started out originally with these cytotoxic chemotherapies drugs like cyclophosphamide which we were giving indiscriminately to patients and Causing a lot of toxicity because we didn't have selectivity to those agents.
• 27:59
  Speaker 0: And then we entered this phase Of You Know anti-cytokine therapies therapies that are more directive less immunosuppressive Where we can get most patients in remission.
• 28:08
  Speaker 0: That's been a wonderful time in rheume etalogy.
• 28:11
  Speaker 0: but we all know those drugs are not curative, right?
• 28:14
  Speaker 0: They're temporizing.
• 28:16
  Speaker 0: So where do we need to go is probably back to cytotoxic therapy but we just need to do it selectively.
• 28:22
  Speaker 0: so if we can find clonal populations of cells that are driving our diseases and exploit some aspect of their biology to selectively kill them... That's really going be exciting because that's gonna get us to where we've wanted to go forever which is cure.
• 28:37
  Speaker 1: And then before I wind up Just one final question Could you maybe just talk about kind of the broader implications off vexus and medicine?
• 28:45
  Speaker 1: So, this idea of somatic mutations in non-malignant disease.
• 28:50
  Speaker 0: Yeah!
• 28:50
  Speaker 0: This is the hardest thing for I think the rheumatology community have gotten their head around that hematology communities are well versed with this.
• 28:57
  Speaker 0: You know...this is a concept where if we look at most rheumatologic diseases they don't run into families or start early life.
• 29:04
  Speaker 0: So the idea of germline genetics, something you inherit from your parents give to your children doesn't make a lot sense with most epidemiology or rheumatology diseases.
• 29:13
  Speaker 0: But the idea is somatic mutation that occurs sometime after conceptualization.
• 29:19
  Speaker 0: so it could be in utero and early childhood but all throughout adulthood and i think this opens up the spot is kind of cancer paradigm but applied to inflammatory diseases you acquire mutation gives a growth advantage.
• 29:35
  Speaker 0: that's that's a malignancy.
• 29:37
  Speaker 0: What if your choir mutation particularly in blood it give us like roth advantage to that blood at the same time activates or makes toxic or inflammatory?
• 29:47
  Speaker 0: then that could drive rheumatologic disease.
• 29:50
  Speaker 0: so this basically, you know, non malignant diseases but the same concept of acquired mutations causing the disease.
• 29:57
  Speaker 0: And if you think about it we are acquiring mutations in every organ system of our body continuously as we age.
• 30:05
  Speaker 0: so on that background is probably very likely that diseases do occur.
• 30:09
  Speaker 0: and there's an emerging list of diseases caused by somatic mutations.
• 30:12
  Speaker 0: things like paroxysmal nocturnal hemoglobinuria single-organ diseases or AVMs have a somatic mutation component.
• 30:21
  Speaker 0: So there's just, this is ripe for discovery.
• 30:24
  Speaker 0: And I think Vexus probably one of the first ones to be found because it's an excellent gene in men.
• 30:29
  Speaker 0: so you only have to deal with one allele and its a massive clone.
• 30:33
  Speaker 0: You know like i said its sixty-to eighty-to ninety percent of myeloid cells has this mutation.
• 30:38
  Speaker 0: It's just giant clones floating around.
• 30:41
  Speaker 0: Where we're gonna go though Is smaller clones The cryptic ones The indolent ones.
• 30:45
  Speaker 0: Those are going to be in lymphocyte populations Not in myeloids.
• 30:49
  Speaker 0: So if you have a clone in the myeloid population, it could produce an auto-inflammatory syndrome.
• 30:53
  Speaker 0: A fever disease.
• 30:55
  Speaker 0: but If you had a clone and lymphocyte population that can produce autoimmune diseases.
• 30:59
  Speaker 0: That may be more familiar to adult rheumatologists who take care of patients with more auto immune spectrum stuff.
• 31:07
  Speaker 0: But to find these is going to challenge because You cant just sequence peripheral blood For vexus ucan its easy to see.
• 31:15
  Speaker 0: If you sequence blood, your not gonna be at the depth of coverage to see this.
• 31:21
  Speaker 0: So we're going have find different ways to find these and I sort of alluded it briefly in some venues.
• 31:28
  Speaker 0: but think found one of these lymphocyclonal forms vasculitis And were just getting ready to kind unleashed on world.
• 31:36
  Speaker 0: try get published.
• 31:37
  Speaker 0: But challenge is how do you find them?
• 31:40
  Speaker 0: Because its a needle and haystack broader spectrum of what these diseases can look like in rheumatology.
• 31:48
  Speaker 1: Brilliant, thank you.
• 31:49
  Speaker 1: we look forward to finding out more about this cryptic disease.
• 31:53
  Speaker 1: I will thank both of you for your time today.
• 31:55
  Speaker 1: Sarah Thank You so much for joining and being enthusiastic about this idea.
• 31:59
  Speaker 1: And Dr Grayson just it's been wonderful To be able to pick your brains About It!
• 32:04
  Speaker 1: As one Of the people who was there from The beginning Your insight is invaluable.
• 32:09
  Speaker 1: So thank you Both For Your Time
• 32:11
  Speaker 0: My Pleasure.
• 32:11
  Speaker 0: Thanks very
• 32:13
  Speaker 1: Much.
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• 32:20
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• 32:47
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