Speaker 1: My name is Sarah Johnson, and I have had lupus
Speaker 1: since I was a teenager. When I was fourteen fifteen,
Speaker 1: I started having this series of fevers, and they were
Speaker 1: kind of a couple days a week once a month,
Speaker 1: and then all of a sudden, they were for a
Speaker 1: whole week each month, and then they just the time
Speaker 1: in between them started getting smaller and smaller. I couldn't
Speaker 1: find any source of infection or reason that I would
Speaker 1: be having any fevers. For some reason, these fevers would
Speaker 1: get extremely high in like one O two, one oh three.
Speaker 1: I would be really nauseous. I wasn't able to eat.
Speaker 1: I wasn't really able to keep food down or liquid down,
Speaker 1: and I ate a lot of popsicles because it was
Speaker 1: the only thing that I could eat for a long time.
Speaker 1: With these fevers would come a lot of soreness. It
Speaker 1: was difficult to get up and walk around, especially in
Speaker 1: my ankles and my knees and my hip. It was
Speaker 1: uncomfortable to sleep. After a while, it just had been
Speaker 1: months of this type of back and forth fevering, not
Speaker 1: being able to keep a lot down, and the fevers
Speaker 1: got high enough and I got weak enough that I
Speaker 1: had to go to the hospital and I stayed in
Speaker 1: the hospital for probably about two months. So I was
Speaker 1: around fifteen at this time, so you know, leaving school
Speaker 1: at the age of fifteen it is extremely traumatic because
Speaker 1: your friends are.
Speaker 2: Pretty much the most important thing to you.
Speaker 1: So going into the hospital, I had to start fluids,
Speaker 1: and this was basically just to get me up to
Speaker 1: a baseline where I felt semi normal again. And then
Speaker 1: with those fluids, I had too many fluids. I had
Speaker 1: pleurisy in my lungs, which is inflammation of the tissue
Speaker 1: around your lungs. So then I had a really difficult
Speaker 1: time breathing and they had to help drain fluids out
Speaker 1: of my lungs and give me LASiS to help me
Speaker 1: kind of shed that fluid. So that was kind of
Speaker 1: the first little bit of my introduction to whatever we
Speaker 1: thought was going on with my body. At the time,
Speaker 1: I didn't know anything about lupus. And at the hospital
Speaker 1: I was at the Children's hospital, they did a lot
Speaker 1: of different tests. They tested me for all sorts of
Speaker 1: different blood disorders, lime disease, rocky mountains, spotted fever, if
Speaker 1: I had a spinal tap to see if I had
Speaker 1: some sort of infection, really anything that you could think of.
Speaker 1: I was having blood drawn all the time, and really
Speaker 1: it didn't It wasn't until I started seeing a rheumatologist
Speaker 1: at the hospital that she started suggesting that it could
Speaker 1: be something called adult onset Stills disease or juvenile Stills disease,
Speaker 1: where you have sometimes when I would have these fevers,
Speaker 1: I would have this under this skin, not quite a rash,
Speaker 1: but it was like a modeling where almost when you
Speaker 1: get a bruise and you have like a speckley red
Speaker 1: under your skin. So I'd have that on the back
Speaker 1: of my upper arms and on the inside of my knees,
Speaker 1: and when I would when I would shower actually is
Speaker 1: when they would get most prominent, so almost like when
Speaker 1: there was heat and kind of inflammation in those areas,
Speaker 1: and so she noticed that as a sign that, oh,
Speaker 1: that's sometimes related to this rheumatoid condition, so maybe that's
Speaker 1: what's going on, and so kind of that was just
Speaker 1: my diagnosis for a long time, and really the only
Speaker 1: way I got better was by staying in the hospital,
Speaker 1: getting tons of fluids and eventually starting a course of
Speaker 1: steroids or pread and zone and taking that for a very,
Speaker 1: very very long time. I think I was probably on
Speaker 1: sixty milligrams or more of premazone for six months to
Speaker 1: a year, and based on all the things that had
Speaker 1: happened to me in the hospital, the stress to my
Speaker 1: body and my immune system for that long, I remember
Speaker 1: having like on my sixteenth birthday, I have pictures of
Speaker 1: me with different colored roots in my hair because my
Speaker 1: hair started growing a different color. So anyways, really that
Speaker 1: time just kind of passed, and then after all of
Speaker 1: this course of medication, I got a lot better. I
Speaker 1: would say the biggest thing that I can remember coming
Speaker 1: out of that was I had very very intense anxiety
Speaker 1: for a long time after that, for a few years,
Speaker 1: and I was fortunate enough to see a therapist who
Speaker 1: focused on chronic diseases, especially with people like my age,
Speaker 1: and just learn how to use a lot of coping
Speaker 1: skills to not be really scared all the time, because
Speaker 1: when you have something like this that you don't know
Speaker 1: where it came from or how it was spurred, you
Speaker 1: never know when it's going to happen again, or what's
Speaker 1: going to cause it, or what you're doing that's going
Speaker 1: to make it harder for you. One big thing is
Speaker 1: stress in my life was very stressful in my preteen years.
Speaker 1: There's a lot going on in my life and at home,
Speaker 1: and you're told to manage your stress, but when you're
Speaker 1: fifteen sixteen, it seems almost impossible. So that took me
Speaker 1: a long time to adjust. But now at thirty five
Speaker 1: years old, I feel like I'm doing a lot better
Speaker 1: with it. So from fifteen sixteen, I didn't really have
Speaker 1: any issues with this. Again, I think probably until I
Speaker 1: was around twenty one. I probably treated my body pretty
Speaker 1: poorly in my twenties, so I just assumed that whatever
Speaker 1: was going on with me was just me being run
Speaker 1: down and tired and started getting fevers again and then
Speaker 1: having a lot of the same issues. So I found
Speaker 1: a new roomatologist at that time basically said, oh, it's
Speaker 1: just this stills disease. You're going to grow out of it.
Speaker 1: Don't worry about it. So I moved on to another
Speaker 1: rheumatologist because I did not believe that whatsoever, And they
Speaker 1: looked at a lot of my past history which the
Speaker 1: previous roomatologists had not done, and said, you know, a
Speaker 1: lot of this really looks like lupus. There's this new
Speaker 1: test out there now where we can search for this
Speaker 1: essentially if you're more likely to have lupus or not,
Speaker 1: and it came back positive. So this is the best
Speaker 1: we can do at trying to figure out if it's
Speaker 1: potentially lupus. But at the end of the day, most
Speaker 1: of the trees treatments for this type of illness are
Speaker 1: the same. So I started hydroxychloroquin or plaquino when I
Speaker 1: was around twenty one, and I've been on it for
Speaker 1: fifteen years now pretty much with very few.
Speaker 2: Issues or side effects.
Speaker 1: I'm at a stage with my loopus where I really
Speaker 1: only seemed to have a flare up every three years
Speaker 1: or so. Seemed like I had a flare up in
Speaker 1: twenty fourteen, twenty fifteen, then again in twenty seventeen, twenty eighteen,
Speaker 1: and then again twenty twenty twenty twenty one, which was
Speaker 1: a very strange time to have a flare up. A
Speaker 1: strange but also very positive time to have a flare
Speaker 1: up because I didn't have anywhere that I had to go,
Speaker 1: you know, I really could focus on taking care of myself.
Speaker 1: I spent a lot of time in my garden. But
Speaker 1: it was a really brutal flare up. The challenge for
Speaker 1: me has been. When you move and you see a
Speaker 1: different rheumatologist, you kind of have to explain your whole
Speaker 1: story to them over and over again. So for anyone
Speaker 1: who has this or has anything similar, being your own
Speaker 1: ad and keeping really good records is crucial because when
Speaker 1: I had this issue again in twenty twenty, I had
Speaker 1: to find a new doctor. I had different insurance at
Speaker 1: that time, and when you're well, you don't think to
Speaker 1: deal with any of this stuff. They came in handy
Speaker 1: when I was sick because I could take all this
Speaker 1: information to my new doctor in twenty twenty and say,
Speaker 1: this feels similar but different, and here's all the information
Speaker 1: that I have. So I stayed on premozone for most
Speaker 1: of the rest of the year, and I finally started
Speaker 1: feeling a lot better. And then phasing out of prednozone
Speaker 1: was equally as difficult, I feel like as going onto
Speaker 1: the prednizone because your body then kind of adjusts to
Speaker 1: this elevated level of incredibleness, which is feeling amazing. So
Speaker 1: since then I've been pretty well. Like I said, I
Speaker 1: was fortunate that I didn't have a lot requiring my
Speaker 1: attention that year. I didn't need to do field work
Speaker 1: for grad school. For a lot of people, those are
Speaker 1: very limiting factors to a disease like lupus, where you
Speaker 1: just can't expect what your schedule is going to look
Speaker 1: like or be able to anticipate these events in your
Speaker 1: life that may need to completely be canceled or changed
Speaker 1: because you don't know when or where you're going to
Speaker 1: have a flare up. Personally, I've chosen probably one of
Speaker 1: the worst fields to be in for someone with a
Speaker 1: chronic inflammatory disorder. I'm a field biologist. I spend a
Speaker 1: lot of time outside in the sun, physically active, but
Speaker 1: I love it and it's what matters to me. So
Speaker 1: I've over the years found ways to have a more
Speaker 1: flexible schedule or a schedule that's more adapted to what
Speaker 1: I need and when I'm capable. I also take really
Speaker 1: good care of myself in terms of wearing protective clothing.
Speaker 1: I treat all of my clothing with sunnguard, and I
Speaker 1: wear long sleeves, and I wear big hats, and I
Speaker 1: wear a ton of sunscreen and so all of those
Speaker 1: things in addition to therapy and you know, making sure
Speaker 1: I keep my stress at a good level and trying
Speaker 1: to get a lot of sleep. So yeah, I guess
Speaker 1: that's most of my life with lucas. I think that
Speaker 1: I'm very fortunate to have whatever version of this chronic
Speaker 1: disease that I have, because I can lead a pretty
Speaker 1: normal life. It's tough when I'm in a flare up,
Speaker 1: but I do feel like over time, I've built this
Speaker 1: kind of anthology of wisdom and knowledge that has helped
Speaker 1: me manage it so much better than I could have
Speaker 1: ever dreamed of when I was fifteen and things really
Speaker 1: felt terrible.
Speaker 3: Wow, like wow, thank you, Sarah, thank you so much
Speaker 3: for sharing your story with us.
Speaker 2: Yeah, Sarah, thank you that, I mean thanks for having
Speaker 2: to go through that by telling us this story and
Speaker 2: then sharing it with everyone. Just yeah, yeah, thanks, We're
Speaker 2: really grateful. Hi. I'm Erin Welsh and I'm Erin Almond
Speaker 2: Updike And this is this podcast will kill.
Speaker 3: You And today if you haven't figured it out, we're
Speaker 3: talking about lupus.
Speaker 2: We are. This is a okay, this is probably the
Speaker 2: what is this our sixth episode? So the sixth time
Speaker 2: this season that we have said it's gonna be a
Speaker 2: big one. Yeah, and we've been right in every case.
Speaker 2: There's a lot to cover here, So should we get
Speaker 2: straight down to business? We should. It's quarantiny time. Excellent.
Speaker 2: What are we drinking this week? We're drinking the Butterfly smash.
Speaker 2: Love this why is the favorite?
Speaker 3: So shout out Sarah love this quarantiny title. She came
Speaker 3: up with it because she's amazing. It's butterfly smash because
Speaker 3: there is a very typical rash that you can see
Speaker 3: in lupus that is often called a butterfly rash.
Speaker 2: But it's a great it's a really good name, it
Speaker 2: really is. And a good drink erin what's in it? Yeah,
Speaker 2: So this is actually a listener suggestion, So thank you
Speaker 2: so much for sending this over because it is delicious.
Speaker 2: So it is a bourbon fizz, so bourbon and then
Speaker 2: strawberry puree and lime juice topped with ginger beer. So refreshing,
Speaker 2: so delightful, so so so so yum.
Speaker 3: And we'll post the full recipe for that quarantine as
Speaker 3: well as our non alcoholic plasy but Rita on our website.
Speaker 2: This podcast will kill you dot com and all of
Speaker 2: our visual media channels. We certainly will. Yeah. On our
Speaker 2: website you can find the things that you can always
Speaker 2: find there transcripts, the sources for each and every one
Speaker 2: of our episodes. We've got links to bookshop dot org,
Speaker 2: to goodreads list to music by Bloodmobile. Just go check
Speaker 2: it out. It's great everything. Yeah. Great.
Speaker 3: We do have a small piece of business to announce
Speaker 3: before we get into the content of this episode, and
Speaker 3: that is that you will notice a slight schedule change
Speaker 3: coming up in our episode, really schedule because I Aaron
Speaker 3: Almann Updike am having another baby and we'll be taking
Speaker 3: a leave of absence for a short time.
Speaker 2: It's amazing. I'm super excited. It's going to be an adventure.
Speaker 2: But Aaron Welsh has covered because she's.
Speaker 3: Got tons of bonus episode content that's going to be
Speaker 3: filling in any gaps.
Speaker 2: So yeah, So episodes will be coming out every other week,
Speaker 2: but instead of one regular season episode every other week,
Speaker 2: it'll be regular season episode two weeks later, bonus episode
Speaker 2: two weeks later regular episode. And this is just for
Speaker 2: a short amount of time, so we'll be back to
Speaker 2: our regularly scheduled programming briefly, all right, Well, any other business,
Speaker 2: I don't think so. I think that we should get
Speaker 2: started on this massive topic. I can't wait right after
Speaker 2: this break.
Speaker 3: So lupus, or as it's more properly called, systemic lupus arithematosis,
Speaker 3: the first question that you may have listeners is what
Speaker 3: is this?
Speaker 2: And the truth of the matter is we still simply
Speaker 2: don't know. Will we have a better understanding forty minutes
Speaker 2: from now, Yeah, yeah, we will for sure for sure.
Speaker 3: But I want to start with a quote which I
Speaker 3: don't do very often, but I read a paper from
Speaker 3: like twenty years ago, was published in two thousand and three,
Speaker 3: and that really just highlighted how little we knew then
Speaker 3: about the path of physiology of lupus, and I was like, well,
Speaker 3: surely when I get to the more recent papers. So
Speaker 3: then there was a paper that came out in twenty
Speaker 3: nineteen in the Lancet that started off strong with this quote.
Speaker 3: Quote Systemic lupus arithematosis is not only the prototypic systemic
Speaker 3: autoimmune disease, but also one of the most heterogeneous illnesses
Speaker 3: treated by physicians.
Speaker 2: End quote. It doesn't really tell you much, doesn't. Nope,
Speaker 2: it doesn't.
Speaker 3: And also just like it really underscores just how okay
Speaker 3: we need to just keep going because it's going to
Speaker 3: be too much Okay, I am a little worried that
Speaker 3: for some people this biology section might feel very unsatisfying,
Speaker 3: But the truth is that that's because lupus is a
Speaker 3: disorder that we still just don't fully understand. And I
Speaker 3: really wonder if we will find in the years to
Speaker 3: come that what we now call loopus or even systemic
Speaker 3: lupus arithematosis, is actually this very very large umbrella under
Speaker 3: which we might have in the future many different disorders
Speaker 3: as we understand more of the genetics and everything that
Speaker 3: underpin this disease.
Speaker 2: But in any case, we will try our best.
Speaker 3: So what I'm going to do is first highlight some
Speaker 3: of the most common symptoms, which there are a lot,
Speaker 3: how we diagnose lupus, what we know so far about
Speaker 3: both the big picture, you know, risk factors and contributing factors,
Speaker 3: as well as the nitty gritty path of physiology of
Speaker 3: what's happening in our bodies in someone with lupus, and
Speaker 3: then at least a little bit about how it's treated
Speaker 3: or managed, which is a lot of ground to cover. So,
Speaker 3: like I said, already, lupus, which is how I'm going
Speaker 3: to refer to it from now on, is a chronic
Speaker 3: systemic autoimmune disease. There are, and I'll mention all of these,
Speaker 3: some other forms of lupus that are sometimes lumped within lupus,
Speaker 3: and sometimes they're very separated, and I'll at least mention
Speaker 3: all of them. But there is cutaneous loopus, which means
Speaker 3: that you might only have skin findings without any systemic symptoms.
Speaker 3: There is a drug induced lupus that is brought on
Speaker 3: by medications, but generally not something that turns into a
Speaker 3: chronic disease. It usually resolves with stopping that medication. And
Speaker 3: then there's also neonatal loopus, which can happen to infants
Speaker 3: that are born to people with lupus.
Speaker 2: Huh.
Speaker 3: But today our focus is sle systemic loopus. Henceforth, again
Speaker 3: I'm just gonna call loopus. And we have covered on
Speaker 3: this podcast a number of other autoimmune diseases in the past.
Speaker 3: We've talked about MS, We've talked about type one diabetes.
Speaker 3: But to refresh everyone, autoimmune simply means that one of
Speaker 3: the main pathologic drivers of a disease is the production
Speaker 3: of antibodies that are attacking one's self rather than only
Speaker 3: attacking non self. And this auto antibody as they're called
Speaker 3: production is associated with a whole bunch of other immune
Speaker 3: system dysregulation that can lead to inflammation and damage to
Speaker 3: various parts of the body. In the case of the
Speaker 3: other autoimmune diseases that we have covered on the podcast,
Speaker 3: for example, MS, it's predominantly just affecting our central nervous
Speaker 3: system right, destroying our nerve axon sheets. Type one diabetes
Speaker 3: is auto antibodies destroying the insulin producing cells of our pancreas.
Speaker 3: These are you can think of as like very targeted,
Speaker 3: localized autoimmune disorders. They're affecting a single organ or a
Speaker 3: single organ system. Lupus, on the other hand, is systemic.
Speaker 3: It does not discriminate, and it has the capacity to
Speaker 3: affect any and every organ or organ system or part
Speaker 3: of our body. And that is what makes it so
Speaker 3: incredibly difficult. It's not the only systemic autoimmune disease, rheumatoid arthritis,
Speaker 3: chogrin syndrome, there are a lot of others, but lupus
Speaker 3: is probably the most heterogeneous and difficult to get a
Speaker 3: handle on. So of course it's the first one that
Speaker 3: we're going to cover on this podcast.
Speaker 2: Uh, tell me what you mean by heterogeneous In this context.
Speaker 3: Let me tell you by going over the symptoms, that'll
Speaker 3: do it. Yeah, And that's really what I mean is
Speaker 3: that the way that this can present, both in terms
Speaker 3: of the symptoms and in terms of the laboratory findings
Speaker 3: that we see very a ton person to person. So
Speaker 3: one person's experience with lupus might be higherly different than
Speaker 3: another person's experience with lupus.
Speaker 2: Okay, So when it comes.
Speaker 3: To the symptoms, because of that, I can't give you,
Speaker 3: like I often do this timeline of events of what
Speaker 3: happens in terms of symptoms, like first we see this
Speaker 3: and then this, Because somebody with loopus can present with
Speaker 3: any or all of the symptoms that I'm going to
Speaker 3: go over. It's unlikely that someone would have all of
Speaker 3: these symptoms at once, but it is entirely possible that
Speaker 3: they could have all or nearly all of them throughout
Speaker 3: their lifetime at different times. So the diagnosis of lupus
Speaker 3: is really challenging. Because of that, it is easy to
Speaker 3: both under attribute symptoms, to not recognize symptoms as related
Speaker 3: to lupus, as well as over a tribute, especially if
Speaker 3: somebody has a previous diagnosis of lupus, to just assume
Speaker 3: that everything someone's experiencing is related only to lupus, like
Speaker 3: a la house.
Speaker 2: So how then is some thing determined to be over
Speaker 2: or under attributed, right, Like, how do you know that
Speaker 2: it's correctly attributed to lupus? Oh, Aaron, if I had
Speaker 2: an answer to that, we don't have any sort of
Speaker 2: cellular diagnostics, so we do for a lot of these.
Speaker 3: So let's get into what some of the most common
Speaker 3: symptoms are and then we can talk about kind of that. Okay, okay, Yeah,
Speaker 3: So one of the most common symptoms that we see
Speaker 3: is arthritis. Arthritis is a major symptom of loopus, with
Speaker 3: about eighty five percent of people with loopus having symptoms
Speaker 3: of inflammation and pain in the joints. Joint involvement is
Speaker 3: actually one of the most universal symptoms of systemic autoimmune diseases.
Speaker 3: Why our joints specifically are so susceptible to this type
Speaker 3: of autoimmune inflammation, we don't know, but they definitely are.
Speaker 3: So Arthritis pain in your joints, especially in the hands,
Speaker 3: in the wrists, but it could be any joint in
Speaker 3: your d higher body. That's one huge one. Then there
Speaker 3: are a whole host of skin manifestations, and these can
Speaker 3: vary widely. I'll talk about some of the most common ones.
Speaker 3: Many of these are brought on or exacerbated by exposure
Speaker 3: to the sun. So a new rash or a new
Speaker 3: skin finding that's brought on after sun exposure is something
Speaker 3: that might make someone think lupus. And as I mentioned
Speaker 3: early on, some of these skin findings are also found
Speaker 3: in people that have cutaneous lupus, arithematosis or cle That
Speaker 3: doesn't necessarily mean that they have any systemic symptoms of lupus,
Speaker 3: so it's it's a lot, but the skin involvement happens
Speaker 3: in again about seventy to eighty percent of people that
Speaker 3: have lupus systemic lupus, and they can be classified by
Speaker 3: how quickly they appear or how long they last. So
Speaker 3: there's some rashes like the malar rash or the butterfly rash.
Speaker 3: This is like a reddish, not very raised rash that
Speaker 3: goes across the nose and onto the cheeks and really
Speaker 3: looks kind of like a butterfly, like if your nose
Speaker 3: was the body of a butterfly, and then your cheeks
Speaker 3: are like the wings. And it doesn't usually go into
Speaker 3: the nasolabial folds like right, interesting, that's your smile lines. Yeah,
Speaker 3: so that's one type of rash that we can see,
Speaker 3: very often brought on by being in the sun or
Speaker 3: by sun exposure. Sometimes the skin findings might be ulcers
Speaker 3: in the mouth or other mucous membranes. You could have
Speaker 3: just disseminated like splotchy red bumps kind of all over,
Speaker 3: or a number of different discrete patches on the skin,
Speaker 3: especially on sun exposed areas, that look round like discoid
Speaker 3: is one very common finding. Maybe a little bit like
Speaker 3: a psoriasis plaque, so something that's like raised and kind
Speaker 3: of scaly. That's a common one. You could also have
Speaker 3: blisters that aren't very superficial but are kind of underneath
Speaker 3: that first layer of skin. There are a few other
Speaker 3: things that we might see. Leveto reticularis one of my
Speaker 3: favorite words. This is a lacy pattern of purple like
Speaker 3: modeling that you might see usually on the lower legs,
Speaker 3: or rainode syndrome, which is where in the cold, the
Speaker 3: tips of your fingers or your toes turn white or
Speaker 3: even blue or purple and it's incredibly painful.
Speaker 2: Those last two, the levito.
Speaker 3: Reticularis and the rain nods are related more to vasospasm
Speaker 3: of blood vessels, but you see those skin manifestations with them.
Speaker 3: And then we also can see hair loss or what's
Speaker 3: called non scarring alopecia, So in various patches you might
Speaker 3: have hair loss or sometimes kind of diffusely see that
Speaker 3: people are kind of losing a lot of hair that
Speaker 3: eventually we'll grow back. It's not causing scarring across the skin.
Speaker 2: And so any one of these things that you've mentioned
Speaker 2: so far, because I know you're not done. I know
Speaker 2: happen sequentially or at the same time, or you see
Speaker 2: one and not the other. It's just a complete mixed bag.
Speaker 2: It's a complete mixed bag. And I'm not even close
Speaker 2: to done if you do.
Speaker 3: Fever is another really common manifestation or something that we
Speaker 3: see a lot. About thirty one percent of people with
Speaker 3: lupus will have fevers at some point with a flare
Speaker 3: or maybe like the first time that they're diagnosed. We
Speaker 3: also can see various forms of saracitis, which are generalized
Speaker 3: inflammation of our sorrosal membrane. So this means the layers
Speaker 3: in our body that are like between organs, so say
Speaker 3: the plura, the lining of your lungs or the pericardium,
Speaker 3: the lining of your heart, or even the lining of
Speaker 3: your abdomen, though that's a little bit less common. So
Speaker 3: what this is going to cause, especially in the case
Speaker 3: of inflammation in the lining of the heart or the
Speaker 3: lining of the lungs, is incredible chest pain, especially what's
Speaker 3: called pluritic chest pain. This pain that gets a lot
Speaker 3: worse if you try and take a deep breath, because
Speaker 3: that's stretching these linings and causing a lot of pain
Speaker 3: because of all of that inflammation. That sounds horrible, I know,
Speaker 3: it's really awful. There's a lot more. Lupus can also
Speaker 3: affect the nervous system, so it can cause neurologic symptoms,
Speaker 3: and these can vary incredibly widely because it's not just
Speaker 3: affecting one particular part of the nervous system or another.
Speaker 3: So it could mean things like seizures, could mean things
Speaker 3: like neuropathies, or having various kind of numbness or tinglings,
Speaker 3: or like unusual sensations because of nerve damage. It could
Speaker 3: mean cognitive dysfunction, severe fatigue, brain fog. Lupus also has
Speaker 3: a significantly increased risk for stroke as well as cardiovascular disease.
Speaker 3: In general, people living with lupus have a twofold increased
Speaker 3: risk for cardiovascular disease and an increased risk of high
Speaker 3: blood pressure. One of the other biggest and most important
Speaker 3: in terms of morbidity and mortality signs or symptoms of
Speaker 3: loopus is what's called lupis nephritis, and this is what
Speaker 3: happens when lupus affects the kidneys. This happens to most
Speaker 3: papers that I read estimated more than half of people
Speaker 3: with lupus, so about sixty percent of people with lupus
Speaker 3: within a decade of their first diagnosis, although some papers
Speaker 3: have slightly lower estimates. But the damage that lupus can
Speaker 3: cause to the kidneys in particular is very significant. So
Speaker 3: lupus nephritis can end up leading to end stage kidney disease,
Speaker 3: which can result in somebody needing dialysis or even a
Speaker 3: kidney transplant. It can also lead to a lot of
Speaker 3: issues with blood pressure because your kidneys are really integral
Speaker 3: in the maintenance of blood pressure. So with lupus nephritis,
Speaker 3: the main way that this is confirmed to be inflammation
Speaker 3: and damage to the kidneys caused by lupus and not
Speaker 3: anything else, which is a question that you asked earlier.
Speaker 3: Aaron is by biopsy, kidney biopsy, and that is something
Speaker 3: that we can do in several of these other cases
Speaker 3: as well. For example, a lot of the skin manifestations,
Speaker 3: we can take a biopsy and look for specific histological
Speaker 3: findings that are associated with lupus. That's not true for everything,
Speaker 3: in part because we don't want to biopsy, you know,
Speaker 3: your heart if we don't absolutely have to, et cetera.
Speaker 3: But when we have some of these findings, we can
Speaker 3: do biopsies and that can tell us a lot about
Speaker 3: whether this is lupus or something different. In terms of
Speaker 3: what the symptoms might be with someone with lupus nephritis,
Speaker 3: what we usually see is protein in the urine or
Speaker 3: sometimes just small amounts of blood or white blood cells
Speaker 3: that are just continuously there in the urine, and then
Speaker 3: other lab findings that are just suggesting general kidney damage.
Speaker 3: But the biopsy is really pretty important to actually look
Speaker 3: at the vessels and see the type of damage that's specific.
Speaker 2: To lupus and what type of damage is that. Yeah,
Speaker 2: let's this is a really good question.
Speaker 3: So that question, Aaron gets really into the nitty gritty
Speaker 3: of the path of physiology of this disease. Right, So
Speaker 3: if we zoom in and look at what is happening
Speaker 3: in your body when you're living with lupus, how exactly
Speaker 3: is this disease causing all of these different effects. We
Speaker 3: do actually know at least a little bit of detail,
Speaker 3: but it's still probably not going to be very satisfying
Speaker 3: herein But the central mechanism of damage, like I mentioned
Speaker 3: when I was just talking about autoimmune diseases in general,
Speaker 3: is this autoantibody production. So in lupus, we're making these
Speaker 3: antibodies that target our own cells or things and structures
Speaker 3: within our own cells. In the case of lupus, it's
Speaker 3: most often antibodies against the nucleus or against our DNA,
Speaker 3: but there are a whole bunch of other specific antibodies
Speaker 3: that can be associated with lupus as well. What happens
Speaker 3: is that these autoantibodies are binding to stuff various things
Speaker 3: our DNA, our nucleus, et cetera in our cells, and
Speaker 3: then they're triggering inappropriate immune responses. So what we see
Speaker 3: are increases in things like B cell activation, remember our
Speaker 3: B cells, or what are making antibodies. We're seeing increases
Speaker 3: in T cell activation as well, because our T cells
Speaker 3: are what are activated often by our antibodies to start
Speaker 3: reacting and blocking off or killing whatever pathogen they're supposed
Speaker 3: to be defending against. And really we can see this
Speaker 3: just generalized pattern of inflammation. The places in our body
Speaker 3: that this inflammation often ends up causing damage very commonly
Speaker 3: are in our blood vessels, but also in any possible
Speaker 3: organ so in our joint space. I know your face
Speaker 3: is so unsatisfied with this exploration.
Speaker 2: Like in our blood vessels that I'm like, Okay, finally
Speaker 2: we're getting down to some like a little bit more
Speaker 2: specifics said, and any other organ it is, though, I
Speaker 2: know it's reality.
Speaker 3: So like in the case of serositis, then this is
Speaker 3: inflammation caused by you know, auto antibodies and generalized white
Speaker 3: blood cell and cytokine production and inflammation that's attacking the
Speaker 3: lining specifically, right, so it's attacking our peracardial cells.
Speaker 2: Right.
Speaker 3: In the case of our kidneys, you have inflammation that's
Speaker 3: attacking the tubules of the kidneys as well as the
Speaker 3: blood vessels that lead into the kidneys.
Speaker 2: But these are not this is not one cell type
Speaker 2: or one target. There are different antibodies targeting different things
Speaker 2: that can be involved. How is this one disease.
Speaker 3: Such a good question, And it goes even further because
Speaker 3: it's not just targeting cells, because the other thing that
Speaker 3: can happen that's really important in lupus is that these
Speaker 3: auto antibodies themselves can lead to what's called immune complex deposition.
Speaker 3: You can think of this as clumps of our highly
Speaker 3: active immune cells, as well as various debris and just
Speaker 3: things that are in our body that ends up sticking
Speaker 3: to the walls of stuff, sticking to the walls of
Speaker 3: our blood vessels, sticking to the tubules of our kidneys,
Speaker 3: getting deposited in our skin, getting deposited in our joints, right.
Speaker 2: Out of the organs. Yeah.
Speaker 3: I like that, except it's not crystals. It's just these
Speaker 3: immune complexes slumps.
Speaker 2: Yeah.
Speaker 3: But these things are going to then cause even more inflammation,
Speaker 3: right because they're going to just continue triggering our immune response.
Speaker 3: And all of these things together, this generalized inflammation, the
Speaker 3: immune complex deposition, the vasculitis, or the inflammation happening in
Speaker 3: our blood vessels, all of these are causing damage to
Speaker 3: whatever organ they're affecting at the time, And like I mentioned,
Speaker 3: there are specific histological changes that we can see in
Speaker 3: some kinds of cutaneous lupus, those skin manifestations, certainly in
Speaker 3: kidney biopsies.
Speaker 2: And I'm not.
Speaker 3: Going to get into the detail of what those look
Speaker 3: like because they're quite honestly, unless you're a histologist, like
Speaker 3: they're very boring.
Speaker 2: It's like this type of die bines blah blah blah.
Speaker 2: All the histologists out there are like shaking their fists, like,
Speaker 2: come on, these are almost.
Speaker 3: Sorry, it's just because I'm bad at histology, that's the
Speaker 3: real answer. But that that's kind of what's happening on
Speaker 3: the inside. In as much detail as I can provide,
Speaker 3: which I know is not is not a satisfying amount.
Speaker 2: I guess I kind of have a question. I'm honestly
Speaker 2: just so taking it all in that it's hard to
Speaker 2: form questions, but I think I do have one, okay,
Speaker 2: and that is, what are some other things that could
Speaker 2: look like lupus or other things that lupus looks like
Speaker 2: ooh oof.
Speaker 3: Aaron, huh yeah, And like how do we even diagnose this?
Speaker 2: Right? Like that's kind of getting at that question or
Speaker 2: the boundaries that solid or are they permeable. They are,
Speaker 2: they're not that solid.
Speaker 3: How one actually gets diagnosed with lupus is a is
Speaker 3: a very difficult question, and that's in part because, like
Speaker 3: you kind of alluded to, there are a lot of
Speaker 3: things that can look like lupus or that lupus can
Speaker 3: look like. But let's kind of maybe go over some
Speaker 3: of the things that might make it seem more like
Speaker 3: lupus and less like, say, an infection, right, Because someone
Speaker 3: might come in with a rash and a fever, and
Speaker 3: that might be their initial presentation that might seem like
Speaker 3: it's an infection. They might also have abnormalities in like
Speaker 3: their blood cell counts, so we might say that they
Speaker 3: have really high white blood cells and those things are
Speaker 3: going to make you think that they have an infection initially, right,
Speaker 3: Or or someone might come in with, you know, generalized
Speaker 3: joint pain in a number of their joints. That could
Speaker 3: be any number of different kinds of arthritis. Not necessarily
Speaker 3: lupus is going to be the first thing that you
Speaker 3: think of. So let's kind of see if we can
Speaker 3: figure out some of it part of the diagnosis of
Speaker 3: lupus that can be helpful is that about seventy percent
Speaker 3: of people with lupus have a relapsing remitting course of disease.
Speaker 3: So that means that they'll have flares of these symptoms
Speaker 3: and then they'll have periods of remission. The issue is
Speaker 3: that flares could be anyone or any combination of those symptoms,
Speaker 3: and they might not be the same every time, and
Speaker 3: so sometimes a flare might be if someone has arthritis,
Speaker 3: they kind of kind of always have at least some
Speaker 3: joint pain. A flare might be a worsening of those
Speaker 3: chronic symptoms that might be a flare, or a flare
Speaker 3: might be a brand new symptom, a new rash that
Speaker 3: you've never had before, with no changes in maybe any
Speaker 3: other symptoms that you may or may not have. So
Speaker 3: there's no perfect way to diagnose lupus, and it often
Speaker 3: takes a really long time to diagnose because of that.
Speaker 2: I was just about to ask if we had numbers.
Speaker 2: I remember the only other one where we've talked about this,
Speaker 2: I think was endometriosis. Yeah, that's a good question.
Speaker 3: I actually didn't see that, like time from initial symptoms
Speaker 3: to diagnosis, I didn't see numbers on that, but I
Speaker 3: would guess it's very long, and it's often many many
Speaker 3: different doctors and specialists before somebody actually gets that diagnosis,
Speaker 3: except in cases when someone presents with maybe very kind
Speaker 3: of classic findings like lupus nephritis and a rash and
Speaker 3: a fever with these specific blood findings, right, if it
Speaker 3: kind of fits a very classic picture, be easier to diagnose,
Speaker 3: But a lot of times it doesn't. But there do
Speaker 3: exist classification criteria. The American College of Rheumatology and the
Speaker 3: European League against Rheumatism, which I think has recently been
Speaker 3: renamed the European Alliance of Associations for Rheumatology I don't
Speaker 3: know anyways, have classification criteria that they updated in twenty nineteen.
Speaker 2: And in general, to meet.
Speaker 3: Criteria for this classification, you have to have a combination
Speaker 3: of symptoms. Right, some of these clinical criteria, it could
Speaker 3: be any various combination, And there's kind of different points
Speaker 3: for different symptoms that are more likely associated with lupus
Speaker 3: versus less likely. Because I did not go over all
Speaker 3: of the possible symptoms, there are more. Then there are
Speaker 3: also immunologic criteria, so specific lab findings that may or
Speaker 3: may not be present and give you kind of points
Speaker 3: on this scale as well.
Speaker 2: Does duration matter duration of of like a symptom during
Speaker 2: a flare up?
Speaker 3: Good question, Not in this particular classification scheme that I
Speaker 3: know of, Okay, Yeah, but certainly like history of past
Speaker 3: flares is going to be a really important thing that
Speaker 3: also isn't necessarily like a point scale, but is going
Speaker 3: to make someone be more suspicious that it is lupus
Speaker 3: versus something else if they've had similar episodes in the past.
Speaker 2: Okay.
Speaker 3: One of the most important lab findings that in this
Speaker 3: classification criteria is the gateway to be able to even
Speaker 3: get a classification of lupus to begin with, is called
Speaker 3: anti nuclear antibody. This is a very general antibody that's
Speaker 3: directed against the nucleus. Some studies say it's present in
Speaker 3: like ninety five to ninety nine point five percent of
Speaker 3: people with lupus, so it's considered very sensitive, although it
Speaker 3: can be negative even in people with lupus, especially if
Speaker 3: it's very well controlled lupus. But anti nuclear antibodies ANA
Speaker 3: are also present in like fifteen percent of people without
Speaker 3: lupus or any other autoimmune disease, as well as in
Speaker 3: plenty of people with other autoimmune diseases, so it's not
Speaker 3: a specific antibody. So then beyond that one, there are
Speaker 3: also a number of other autoantibodies that do tend to
Speaker 3: be more specific that we usually only see in loopus,
Speaker 3: but they're not always present in loopus.
Speaker 2: I mean, I know erin I know.
Speaker 3: Yeah, So it's unsurprising that it's difficult to diagnose, incredibly
Speaker 3: frustrating if you're just living with joint pain, if you're
Speaker 3: living with chronic fatigue, if you're living with all of
Speaker 3: these symptoms that you don't have an answer for yet, right, Yeah,
Speaker 3: So I guess the next question that I wanted to
Speaker 3: try and answer is like what causes this?
Speaker 2: Not on the you know, cellular.
Speaker 3: Level, but like on the big picture level, what do
Speaker 3: we know about the risk factors and all of that.
Speaker 3: We know that there is absolutely a huge amount of genetic.
Speaker 2: Basis to loopus.
Speaker 3: There is an increased in frequency in twin studies, there's
Speaker 3: an increased risk in siblings. But it's definitely a polygenic risk.
Speaker 3: There are dozens or more different genes that have been
Speaker 3: identified to contribute to increased risk of loopus, and in
Speaker 3: some rare cases there have been like monogenic so like
Speaker 3: one gene susceptibility, but a lot of times what we
Speaker 3: see is that it actually is multiple genes, multiple genetic
Speaker 3: changes that are necessary prior to resulting in loopus.
Speaker 2: If that makes sense. What do these genes do? Are
Speaker 2: they all doing the same thing or are they doing
Speaker 2: a lot of different things?
Speaker 3: Great question, there's a lot. So they are doing a
Speaker 3: lot of different things. But in general they're all related
Speaker 3: to our immune response. So a lot of the genes
Speaker 3: that we've identified are related to our major histocompatibility complexes
Speaker 3: or various human leukocyte antigen changes or polymorphisms. So we
Speaker 3: see these all kind of being related to the propensity
Speaker 3: to develop auto antibodies and like immune system regulation for
Speaker 3: the most.
Speaker 2: Part, Aaron, do other mammals get lupus? I don't know.
Speaker 2: Should we do a quick google? Yeah, let's do a
Speaker 2: quick goog. Yes, that was a very quick goog.
Speaker 3: Well, like first line sees various animals such as cats, rats, dogs, hamsters,
Speaker 3: guinea pigs, rabbits, horses, minx pigs, and primates have been
Speaker 3: described lupus like phenotype. So I don't know if it's
Speaker 3: exactly the same.
Speaker 2: So interesting, what unites every one of these What is.
Speaker 3: Our immune systems? I guess I mean yeah, but ugh,
Speaker 3: I will I'll post this paper that I've found real quick.
Speaker 3: Obviously haven't read it, but looks interesting. Back to genes, Yeah,
Speaker 3: back to genes or rather other things that we can
Speaker 3: get into about the kind of causes of lupus or
Speaker 3: risks for lupus. There is also some good evidence that
Speaker 3: there are associations with lupus and estrogen and testosterone metabolism.
Speaker 3: Testosterone to a lesser extent, estrogen to a larger extent,
Speaker 3: so some of the evidence that we have for this.
Speaker 3: In general, lupus is significantly more prevalent in females. Ninety
Speaker 3: percent of people who get diagnosed with lupus are assigned
Speaker 3: female at birth. And also people with Kleinfelter syndrome, which
Speaker 3: is a genetic condition where someone is born with forty
Speaker 3: seven xxy chromosomes so an extra X chromosome have an
Speaker 3: increased risk for lupus, and people who are born with
Speaker 3: Turner syndrome, which we covered last season, who are We
Speaker 3: talked about it a lot of different possible phenotypes, but
Speaker 3: in general, missing one X chromosome have a lower risk for.
Speaker 2: Lupus, So it's definitely got to be some sort of
Speaker 2: a dose thing with the X chromosome and estrogen.
Speaker 3: Right, So there's a lot of evidence that there must
Speaker 3: be at least some degree of kind of X linkage,
Speaker 3: that is that a lot of these genes that may
Speaker 3: be involved are located on the X chromosome, and or
Speaker 3: having two copies rather than one copy of this X
Speaker 3: chromosome somehow is part of this inherent risk. But again,
Speaker 3: it's not sufficient to cause lupus because plenty of people
Speaker 3: with multiple X chromosomes don't have lupis, so it's fascinating.
Speaker 3: We also can see a risk specifically associated with estrogen,
Speaker 3: where we see sometimes an increase in flares in people
Speaker 3: that are taking exogenous estrogen things like birth control or
Speaker 3: hormone replacement therapy. So there's some thought too that it
Speaker 3: could be alterations in either estrogen metabolism or the hypothalamic
Speaker 3: pituitary axis, which is the axis between our brain and
Speaker 3: our gonads that kind of regulates sex hormone production in general.
Speaker 3: So there's a lot of potential genetic components that we
Speaker 3: don't fully understand but we know are really fascinating and
Speaker 3: interesting and need for their research, but there are also
Speaker 3: likely a lot of environmental factors that work in combination
Speaker 3: to then produce the disease that we know of as lupus.
Speaker 3: When it comes to environmental factors, we don't have one. Course,
Speaker 3: in our MS episode, we spent a lot of time
Speaker 3: talking about EBV infection in the context of trying to
Speaker 3: identify like the one environmental thing, the one exposure that
Speaker 3: might result in MS. Unsurprisingly, for a disease as heterogeneous
Speaker 3: as lupus, we don't have one, and I don't know
Speaker 3: that we'll ever have just one.
Speaker 2: A few things that.
Speaker 3: We know are associated with either flares or with lupus
Speaker 3: diagnosis in general are UV light, So exposure to the
Speaker 3: sun is strongly associated with both the onset of symptoms
Speaker 3: as well as with flares. There's some thought because I
Speaker 3: can see your face being like what why?
Speaker 2: Hell? Well? Also, wasn't that the opposite with MS there
Speaker 2: was a latitudinal gradient. There was a latitude in no ingradient.
Speaker 2: That's fascinating.
Speaker 3: Yeah, But there's some thought that in the case of loopus,
Speaker 3: it's the UV light damage to our skin cells because
Speaker 3: there's a lot of skin manifestations in loopus that then
Speaker 3: ends up causing like increased inflammation and increased antibody production.
Speaker 3: That that's the kind of mechanism there. And then the
Speaker 3: only other two things that have been associated with an
Speaker 3: increased risk of loopus are smoking, so like cigarette or
Speaker 3: tobacco smoking. And then, like I mentioned briefly, there are
Speaker 3: a whole bunch of different medications in almost every medication class,
Speaker 3: like anti arrhythmic medications, blood pressure medicines, anti tuberculosis medicines,
Speaker 3: like over one hundred different medicines that can cause a
Speaker 3: drug induced lupus, but that loopus generally doesn't lead to
Speaker 3: systemic loopus aerythematosis what okay?
Speaker 2: So, like I have a question about these other lupuses?
Speaker 2: Uh huh? What makes them all loopus?
Speaker 3: So we see similar antibody production, okay, and then we
Speaker 3: see similar signs and symptoms oka and laboratory findings.
Speaker 2: Yeah, for drug induced how does that happen? And how
Speaker 2: long does that take or how long does it last?
Speaker 3: It usually doesn't happen unless someone has been on a
Speaker 3: medication for a pretty prolonged period of time. So it's
Speaker 3: not like I started a med and then I got lupus,
Speaker 3: like right, away. It's usually someone who's been on a
Speaker 3: medicine for a very long time, months if not years,
Speaker 3: and then it usually goes away within six months of
Speaker 3: stopping the medication. So if someone, for example, comes in
Speaker 3: with all of these symptoms that look a lot like lupus,
Speaker 3: then one of the first things to do is look
Speaker 3: through what medicines they're taking and say, is there any
Speaker 3: way that this could have just been a drug induced
Speaker 3: lupus versus you know, kind of true lupus or systemic loopus.
Speaker 3: So if you see numbers for lupus in general, that
Speaker 3: means systemic lupus arithematosis, Okay, drug induce lupus is always
Speaker 3: going to be kind of separated out from that. I
Speaker 3: don't have numbers on like how many cases of that
Speaker 3: a year, et cetera. When it comes to cutaneous loopus,
Speaker 3: about ten to twenty five percent of people who have
Speaker 3: cutaneous loopus will then go on to develop systemic loopus,
Speaker 3: so it's actually pretty small amount. But like I mentioned,
Speaker 3: about seventy to eighty percent of people with systemic loopis
Speaker 3: will have some kind of skin manifestation. Okay, and then
Speaker 3: there's the last one that I hadn't even mentioned yet,
Speaker 3: which is neonatal lupus. Yeah, and this happens due to
Speaker 3: a few different types of antibodies, not every possible type
Speaker 3: of lupus antibody, crossing the placenta during pregnancy and then
Speaker 3: being present in the fetus. So once the baby is born,
Speaker 3: those autoantibodies that are already present can lead to liver
Speaker 3: problems or problems with their blood or platelet function That
Speaker 3: tends to be transient and usually resolves within a few months,
Speaker 3: as those autoantibodies are kind of just like getting out
Speaker 3: of the system because remember that baby hasn't made those
Speaker 3: antibodies themselves, they were passed through the placenta. However, the
Speaker 3: most dangerous thing that neont loopus can result in is
Speaker 3: complete heart block, which means that the electrical system of
Speaker 3: their heart isn't working correctly. This is very very rare,
Speaker 3: but does end up causing damage earlier to the point
Speaker 3: where these babies often need pacemakers eventually. And I don't
Speaker 3: have an exact number on how rare, but in general,
Speaker 3: neonatal loopus is very rare. Though loopus in general can
Speaker 3: have huge effects on pregnancy and can sometimes make it
Speaker 3: very difficult to become pregnant or can result in recurrent
Speaker 3: miscarriage and things like that as well.
Speaker 2: What is the average age of onset for loopus symptoms?
Speaker 2: Great question.
Speaker 3: Fifteen to forty four, so reproduct of age and again
Speaker 3: vastly more common in people assigned female at birth. So
Speaker 3: that's kind of most of what I've got for the
Speaker 3: biology erin. I don't know if that was long enough.
Speaker 2: I mean, I have a feeling that you could double
Speaker 2: the length and it would still be unsatisfying. Well, I
Speaker 2: don't want to say unsatisfying, because I do feel like
Speaker 2: I learned a lot and I have a clearer picture.
Speaker 2: But the fault does not lie with you, with you
Speaker 2: where we stand in lupus research today, which is also
Speaker 2: a lot of people are doing great work, but it's
Speaker 2: just a really challenging disease. It is, it really is.
Speaker 3: I will briefly mention different forms of treatment. In general,
Speaker 3: the mainstays of therapy for lupus are various forms of
Speaker 3: immunosuppression in one form or another, and this is to
Speaker 3: reduce both the incidents of flares as well as in
Speaker 3: some cases the classification now is to get to a
Speaker 3: low disease state where you just have a low amount
Speaker 3: of kind of overall inflammation and damage that's being caused
Speaker 3: because sometimes we can't induce complete remission of symptoms, right.
Speaker 3: And there's a whole combination of medicines that are used,
Speaker 3: and they have a number of different effects on the
Speaker 3: immune system. Some like hydroxyd chloroquin actually don't just suppress
Speaker 3: overall the immune system, but rather work on immunomodulation, which
Speaker 3: is really interesting. Then there's things like mycophenolate or methotrexate,
Speaker 3: which are generally causing immunosuppression. And then of course steroids
Speaker 3: corticosteroids that are general anti inflammatories, very effective, but a
Speaker 3: huge amount of side effects, and so in general these
Speaker 3: are for flair suppression rather than like long term use.
Speaker 3: And then there's a huge area of research that I'll
Speaker 3: talk more about later into biologics, things like monoclonal antibodies
Speaker 3: to treat autoimmune diseases in general and lupus in specific.
Speaker 3: There is one that has been approved for lupus. It's
Speaker 3: called belim mumab belimumab, and it targets B cells and
Speaker 3: essentially just kills them.
Speaker 2: And B cells are the ones that make antibodies.
Speaker 3: So that's the only kind of specific biologic medication that
Speaker 3: we have, though there are a couple others that are
Speaker 3: sometimes used off label for lupus too.
Speaker 2: It's a lot. I still feel like I wish I
Speaker 2: knew so much more. I mean, I think everyone wishes
Speaker 2: that everyone knew so much more.
Speaker 3: Well, so tell me arin mm hmm. I mean we
Speaker 3: know a lot considering we do, so how did we
Speaker 3: get here? Where did this come from? And how did
Speaker 3: we end up here where we're at right now twenty
Speaker 3: twenty three?
Speaker 2: Correct? Wow, Okay, no problem, A easy question. I'll get
Speaker 2: right to it right after this break. The history of
Speaker 2: lupus is largely a history of discovery of recognition, and
Speaker 2: it's one that's far from over because we still don't
Speaker 2: know precisely how lupus works, much less the ultimate cause,
Speaker 2: as we you know, learned during the biology section, and
Speaker 2: we do know a lot more now than we did
Speaker 2: in the past. But I don't think that anyone familiar
Speaker 2: with lupus, or anyone who just listened to the biology
Speaker 2: section would say, Yep, you know, not much more to
Speaker 2: do here. We've pretty much got it all figured out.
Speaker 2: Can you imagine, I know, right, And so in the
Speaker 2: history section, what I want to do is take us
Speaker 2: through how we came to recognize and understand this disease
Speaker 2: in a broad sense. But as I was putting my
Speaker 2: notes together, I got to the part where a clinical
Speaker 2: picture of systemic lupus arithematosis had been established through years
Speaker 2: of descriptions and observations, and people had started to look
Speaker 2: for the underlying cause of this autoimmune disease in terms
Speaker 2: of the path of physiology and so on. And I realized, wait, like,
Speaker 2: I'm taking a huge part of this history for granted,
Speaker 2: when researchers began to search for what caused this disease
Speaker 2: on a cellular level, they came to recognize that it
Speaker 2: was an autoimmune disease. But how did that concept of
Speaker 2: autoimmunity come to be? Oh gosh, I don't know, Eric,
Speaker 2: How did people learn what the immune system was? And
Speaker 2: when did they first notice that things maybe didn't always
Speaker 2: go as planned. We've covered germ theory a thousand times
Speaker 2: on the podcast, and that makes sense given that we
Speaker 2: started out as an infectious disease only podcast. But I
Speaker 2: can't remember, and I don't think that I have ever
Speaker 2: talked at least at any great length about the immune
Speaker 2: system or especially the growing study of autoimmune diseases. Definitely,
Speaker 2: not maybe a little in like our vaccines episode, Yeah maybe,
Speaker 2: but that's it, and not autoimmunity for sure. Yeah, And
Speaker 2: I don't think I even talked about that in diabetes
Speaker 2: or multiple sclerosis episodes. And so today what I want
Speaker 2: to do is take us through this history of how
Speaker 2: we filled in this concept of systemic lupus arithematosis as
Speaker 2: we have it largely today. I mean, I probably won't
Speaker 2: take us all the way through the twentieth century, but
Speaker 2: then I also want to step back to ask how
Speaker 2: we formed this concept of autoimmunity in the first place,
Speaker 2: and then at the end I might sprinkle a bit
Speaker 2: of evolutionary biology in the mix. Oh love it all right,
Speaker 2: So let's get started. Some histories of lupus start with
Speaker 2: a shout out to our main man, Hippocrates, or at
Speaker 2: least the texts that bear his name, written around four
Speaker 2: hundred BCE, suggesting that the description in these texts of
Speaker 2: cutaneous ulcerations referred to as herpes estheomenos, points towards the
Speaker 2: symptom of Lupuskay. Other histories appear to think that might
Speaker 2: be a bit of a stretch, because they tend to
Speaker 2: start in the tenth century CE, when Hebernus of Tours
Speaker 2: use the word lupus to describe a particular disease for
Speaker 2: the first time in his biography of Saint Martin, and
Speaker 2: in this he describes how Saint Martin, who lived in
Speaker 2: the fourth century CE, so like six hundred years before,
Speaker 2: treated the Bishop of Liege who was suffering from a
Speaker 2: disease thought to be the loopis we know today. So
Speaker 2: that's like the first description. Okay, why the word lupus?
Speaker 2: I was going to ask you that, Okay, okay, Well,
Speaker 2: the word lupus comes from the Latin word for wolf, right, yeah,
Speaker 2: question question over? Question answered? No, not at all. Well,
Speaker 2: the question of why wolf was used for the name
Speaker 2: of this disease is a little bit trickier to answer.
Speaker 2: In general, there seemed to be two ideas for why
Speaker 2: why lupus why wolf? One is that the facial rash
Speaker 2: seen in some of these cases resembles a wolf like bite, oh, okay,
Speaker 2: And the other is the wolf like way the rash
Speaker 2: seems to gnaw away at the flesh of the person.
Speaker 2: Oh gosh, that sounds awful. Yeah, But having not personally
Speaker 2: witnessed what a wolf's bite looks like or felt the
Speaker 2: gnawing of a wolf bite itself, I don't think I
Speaker 2: can really say whether or not lupus is an accurate
Speaker 2: word or an accurate match. But anyways, apparently the name
Speaker 2: was catchy enough because it's still the one that we
Speaker 2: use today, Although the lupus that was used historically, like
Speaker 2: this person had lupus, or this rash was lupus or
Speaker 2: something that, you know, we may look back at that
Speaker 2: and go, Okay, that likely wasn't lupus.
Speaker 3: Right that what they called lupus then, isn't necessarily what
Speaker 3: we call lupus today exactly.
Speaker 2: Yeah. Until almost the nineteenth century, the word lupus seemed
Speaker 2: to be used to refer to ulcers and boils in
Speaker 2: the lower extremities, whereas facial ulcers were called by the
Speaker 2: term that Hippocrates used so herpes stheomenos, or a Latin
Speaker 2: phrase which translated means touch me. Not interesting. Yeah. In
Speaker 2: the late eighteenth and early nineteenth centuries, though, we begin
Speaker 2: to see the definition of lupus change in seventeen ninety,
Speaker 2: a British dermatologist named Robert Willen used the term to
Speaker 2: describe any progressive, destructive lesions on the face or nose. Also,
Speaker 2: I don't know why so many of the texts specified
Speaker 2: face or nose, like, isn't the nose part of the face?
Speaker 2: And I'm serious, that's a really good question.
Speaker 3: I have no idea why. I mean, I don't think
Speaker 3: I would separate it. What do they mean by face?
Speaker 2: I don't know. Is your forehead part of your face?
Speaker 2: I mean I would say yes, but according to these people,
Speaker 2: who knows anyway. A few decades after this we get
Speaker 2: the first clear description of lupus arithmatosis by Laurent Theodor Biet,
Speaker 2: under the term arithema centrifugum. But it was one of
Speaker 2: Biet's students, Pierre Kazanov, that coined the term lupus arithematosis
Speaker 2: in eighteen thirty three. He described it as quote a
Speaker 2: rare condition which appears most frequently in young females who
Speaker 2: are otherwise healthy. Attacking the face, chiefly, round red patches
Speaker 2: slightly elevated about the size of a shilling, gradually increase
Speaker 2: in size and sometimes spread over the greater part of
Speaker 2: the face. The edges of the patches are prominent, and
Speaker 2: the center, which retains its natural color, is depressed. There
Speaker 2: is heat and redness, but no pain or itching. It
Speaker 2: is essentially a chronic affliction, though its appearance would indicate otherwise.
Speaker 2: Seems to refer to discoid lupus, at least according to
Speaker 2: the paper I read, Yeah, potentially in terms of ideology. Remember,
Speaker 2: this is a time when the humoral theory of disease
Speaker 2: still ruled, and disease was thought to be as much
Speaker 2: about the disposition of the individual person as it was
Speaker 2: about an actual physiological process. So Kazanov thought that especially
Speaker 2: quote young soft women lacking energy and vitality with poor
Speaker 2: capillary circulation were especially prone to lupus arithematosis end quote.
Speaker 2: I know an issue, Okay, I mean, what did you expect?
Speaker 2: It was the eighteen hundreds, Like yeah, Kazanov, Biet and
Speaker 2: another of Biet's students, Henry Schadel, suggested that lupus should
Speaker 2: be divided into three different classes of severity. Number one
Speaker 2: lupus that only destroys the top layers of the skin.
Speaker 2: Number two lupus that destroys deeper layers and number three
Speaker 2: lupus with hypertrophy. A few decades later, Ferdinand von Hebra,
Speaker 2: a physician from Vienna, described two different types of rash
Speaker 2: patterns seen with lupus arithematosis. He described a disc like
Speaker 2: rash and a rash made up of confluent, smaller regions.
Speaker 2: He was also the first to note that the distribution
Speaker 2: of the facial rash resembled a butterfly ooh. Later another
Speaker 2: researcher called it batwing form. If you like that one
Speaker 2: more so up to you. A side note, I loved
Speaker 2: this fun fact. Hebra, the s guy that discovered it.
Speaker 2: His coat of arms contains an elephant, two fish, a
Speaker 2: red wolf, and a pen, each of which represents his
Speaker 2: work on elephant tieis ichthyosis for the fish, lupus arithematosis
Speaker 2: with the wolf, and his skills as a medical author.
Speaker 2: How cute is that? I love that? I know? Anyway.
Speaker 2: The first half or so of the eighteen hundreds mostly
Speaker 2: involved researchers more thoroughly describing the lesions and ulcers that
Speaker 2: were involved in lupus arithematosis, and also demonstrating that they
Speaker 2: were not caused by tuberculosis. Or syphilis, which was a
Speaker 2: very popular belief at the time and also one that
Speaker 2: continued to be debated. Where is The later part of
Speaker 2: the eighteen hundreds shone a light on the systemic nature
Speaker 2: that could be present with this disease, and this was
Speaker 2: largely done by Moritz Caposi. Yes, that Caposi, that Cauposi.
Speaker 2: Okay of Caposi, sarcote, I guess we should specify. Yeah, yeah,
Speaker 2: he also he was Hebra's son in law. What I know,
Speaker 2: isn't that wild? I love it? Anyway. Capose noted that quote,
Speaker 2: experience has shown that lupus arithematosis may be attended by
Speaker 2: altogether more severe pathological changes, and even dangerous constitutional symptoms
Speaker 2: may be intimately associated with the process in question, and
Speaker 2: that death may result from conditions which must be considered
Speaker 2: to rise from the local malady end quote. All right,
Speaker 2: there you go. So it's just so interesting to me,
Speaker 2: Aaron that this, Yeah, yeah, it's interesting sort of the progression,
Speaker 2: the sequence of the progression of knowledge, because Capose, I think,
Speaker 2: may have been the first one to point out some
Speaker 2: of these constitutional symptoms like nodules, adnitis, fever, weight loss,
Speaker 2: and the arthritis symptoms that often happened. He also differentiated
Speaker 2: discoid lupus from disseminated lupus after Caposi's description of systemic
Speaker 2: lupus arithematosis. Other physicians like William Osler, whom I know
Speaker 2: that we've mentioned before. He's kind of a big deal
Speaker 2: in the history of medicine in the US, sort of
Speaker 2: like one of the quote unquote founding fathers of Johns
Speaker 2: Hopkins Medical School.
Speaker 3: Yeah, we've definitely talked about him, but I can't remember why.
Speaker 2: I can't either, and I meant to look it up
Speaker 2: and I forgot. He's done a lot though, and he's
Speaker 2: done a lot. Yeah. He basically he was one of
Speaker 2: the people that majorly changed the medical training requirements in
Speaker 2: the early twentieth century. And there's probably a lot that
Speaker 2: we could talk about in terms of that, but anyway,
Speaker 2: be a whole episode. Yeah, post residency please. Yeah. So,
Speaker 2: Ostler and other physicians began observing cases of the disease
Speaker 2: in their patients and further filling in the clinical picture
Speaker 2: of this disease, the photosensitive nature of the rash, the
Speaker 2: occasional kidney heart or lungen involvement prognosis, and some treatment options.
Speaker 2: The first treatment that people tried out that actually seemed
Speaker 2: to have a positive effect was quinine in eighteen ninety four,
Speaker 2: but the real change came in the nineteen forties when
Speaker 2: Philip Hench successfully treated certain rheumatic and non rhumatic conditions
Speaker 2: in his words, one of which was lupus with cortisone
Speaker 2: and act so add no cordicotropic hormone, and Hench ended
Speaker 2: up being awarded a Nobel Prize for his work on
Speaker 2: this in nineteen fifty. Then anti malarials came back in
Speaker 2: play around this time, with quinocrine chloroquine and hydroxic chloroquin
Speaker 2: found found to be useful in suppressing both systemic and
Speaker 2: cutaneous forms of lupus. And since then, since the nineteen
Speaker 2: fifties or so, we've seen many, many, many more medications
Speaker 2: and treatment strategies for lupus come onto the scene, which
Speaker 2: you've talked about, Aaron. Maybe not as many as you
Speaker 2: might hope or expect, but some of them have been
Speaker 2: focused more like you said, on immunomodulation, which is partly
Speaker 2: because our understanding of the pathophysiology of this disease has improved,
Speaker 2: and the key to this understanding started really with the
Speaker 2: discovery of the LE cell by Malcolm Hargraves, Robert Morton,
Speaker 2: and Helen Richmond in nineteen forty eight. Lee means lupus arethematosis.
Speaker 2: It's also sometimes called the hart Graves cell. Okay, And
Speaker 2: what this discovery did was allow for a test for
Speaker 2: sl if you look for the presence of LE cells,
Speaker 2: and you've got your confirmation except for the fact that
Speaker 2: LE cells are not specific to just systemic lupus arethematosis.
Speaker 2: But it meant that you could diagnose milder forms of lupus,
Speaker 2: which had been more difficul to do in the past.
Speaker 2: But beyond this practical and really incredible application of LE cells, though,
Speaker 2: was the significance that they held for the way this
Speaker 2: disease worked. Because these cells demonstrated that autoimmunity was involved
Speaker 2: in lupus, the idea that the body could attack itself
Speaker 2: was beginning to take shape during this period, with tremendous
Speaker 2: implications for understanding several many other diseases that had remained
Speaker 2: like almost mysteries up to this point. And so now
Speaker 2: I want to take us through a brief tour of
Speaker 2: how we came to terms with this concept. With the caveat,
Speaker 2: of course, that this is a brief tour, not a
Speaker 2: comprehensive story of autoimmunity discovery and research. I can't wait.
Speaker 2: The term autoimmune was not used until nineteen fifty one. Cool,
Speaker 2: and it was only in nineteen fifty seven that the
Speaker 2: WORL autoimmunity was coined.
Speaker 3: I can't tell if I feel like that is earlier
Speaker 3: or later than I expected.
Speaker 2: I really don't know. I think I was shocked. It
Speaker 2: felt so so recent because that was nearly a century
Speaker 2: after germ theory was first proposed and began to sort
Speaker 2: of take hold.
Speaker 3: Yeah, but it also kind of makes sense that, like
Speaker 3: it's a really complicated piece to be able to figure out.
Speaker 2: So it's really complicated and it's counterintuitive, right, So I mean,
Speaker 2: oh yeah, I mean, and I'm not I'm not blaming
Speaker 2: these figure it out earlier. Yeah, what's wrong with you?
Speaker 2: Come on? But I do think that it's just so
Speaker 2: interesting to also sort of like watch this progress of
Speaker 2: how this concept was formed. So let's let's get into it.
Speaker 2: I can't wait. But first I wanted to point out
Speaker 2: that the idea of autoimmunity parallels what was in pre
Speaker 2: germ theory. Times, the dominant idea of disease development the
Speaker 2: humoral theory of disease. Right, I'm sure listeners of the
Speaker 2: podcast are familiar with the humoral theory, but just in case,
Speaker 2: disease was thought to arise due to an imbalance in
Speaker 2: one of the bodily humors yellow bile, black bile, blood,
Speaker 2: and phlegme. So like too much of one humor or
Speaker 2: not enough of another, or a blockage of one kind
Speaker 2: whatever those sorts of things could lead to disease. And
Speaker 2: what caused too much of one or not enough of another,
Speaker 2: I mean, could be anything, including a predisposition that was
Speaker 2: inherited from your parents, Okay, And so when people started
Speaker 2: recognizing immune system disorders like two weak or strong of
Speaker 2: a reaction reacting to yourself, this kind of harkened back
Speaker 2: to the internal balance driven humoral theory of disease. And
Speaker 2: I wonder whether this, you know, throwback idea or this
Speaker 2: like feeling of it being a throwback idea contributed to
Speaker 2: people being more resistant to the idea of autoimmunity, at
Speaker 2: least initially. And also I think this very late eighteen
Speaker 2: hundred's early nineteen hundreds denial that we could be anything
Speaker 2: less than perfect, that humans were not the pinnacle of
Speaker 2: evolution or you know, like we have reached the maximum.
Speaker 2: How could our bodies fail us? It's not possible. But
Speaker 2: also the introduction of germ theory had reframed disease so
Speaker 2: that it became a battle us versus them. And think
Speaker 2: about the language that we use when we talk about
Speaker 2: infectious diseases, wage of war against these microbes. We fight
Speaker 2: off infection, microbial invaders. And this language of war of
Speaker 2: our bodies fighting an external threat emerged with germ theory
Speaker 2: in the mid to late nineteenth century when it seemed
Speaker 2: like it was really only a matter of time before
Speaker 2: every clinically recognized disease was linked to a particular microbe.
Speaker 2: And this shift in the perception of disease was happening
Speaker 2: at a time when medicine was becoming overall less personalized,
Speaker 2: less about talking to the person and listening to the
Speaker 2: person that you were trying to help, but instead looking
Speaker 2: for signs of disease, measuring, culturing, testing, seeing the disease
Speaker 2: versus seeing the patient, which was I feel like we've
Speaker 2: talked about this in a number of episodes erin absolutely
Speaker 2: we have, and of course, this wasn't true across the board,
Speaker 2: especially when microbes couldn't be found for certain illnesses, and
Speaker 2: one of the pockets where patient centered medicine remained was
Speaker 2: in what we would come to recognize as autoimmune disease,
Speaker 2: where years of looking hadn't been able to conclusively link
Speaker 2: a specific microbe to MS, although, as we talked about,
Speaker 2: maybe we're getting there, or rheumatoid arthritis or lupus, although
Speaker 2: remember when I mentioned lupus was thought to be related
Speaker 2: to syphilis. The Washerman test, when that was developed specifically
Speaker 2: to test for syphilis, many people with lupus showed false positives,
Speaker 2: and I'll talk a little bit more about that in
Speaker 2: a second, but that further confused the issue. But when
Speaker 2: people were finding specific pathogens for specific diseases like tuberculosis
Speaker 2: or plague, or finding that a vaccine worked even without
Speaker 2: isolating the pathogen like rabies, what did they think was
Speaker 2: happening inside of our bodies during this fight or battle
Speaker 2: or war? Yeah? By how did they think vaccines worked?
Speaker 2: Or even more simply, how did they think people went
Speaker 2: from being sick to not sick? Yeah? This question was
Speaker 2: still largely unanswered at the turn of the twentieth century.
Speaker 3: I feel like that just makes sense to me because
Speaker 3: it's like, first they did something and they were like, oh, this,
Speaker 3: this does the thing that we wanted to do, and
Speaker 3: then later way after that is when they figured out
Speaker 3: like how it actually did that, and so yeah, oh man.
Speaker 2: It's it is. I just love thinking about the sequence. Yeah,
Speaker 2: it's really fun. And in the previous decades, I mean,
Speaker 2: people had been working on this question. You have Pasture Mechnikov,
Speaker 2: Erlik and many others that proposed various hypotheses like a
Speaker 2: person became immune when the bacteria had consumed all of
Speaker 2: the substrate in the body that it could grow on,
Speaker 2: or our circulating cells swallowed and destroyed the invading bacteria
Speaker 2: or parasites, a process called phagocytosis. We do that, we
Speaker 2: do that, or Aerlich's idea that there is some humoral element,
Speaker 2: which he called antibodies, circulating in our blood serum that
Speaker 2: defends against invaders, recognizing not self from self Airlik for
Speaker 2: the wind, Airlic for the wind, and he developed this
Speaker 2: idea in the eighteen nineties by conducting experiment after experiment
Speaker 2: observing what happened when he applied toxins and antitoxins to
Speaker 2: animal tissues in test tubes. He proposed that our cell
Speaker 2: membranes naturally contain antitoxins or antibodies that are highly specific
Speaker 2: and bind tightly and irreversibly to foreign substances, which he
Speaker 2: called antigens that have been introduced. He then speculated that
Speaker 2: once this first binding occurs, it triggers the production of
Speaker 2: more of those antibodies. He also included in this process
Speaker 2: something he called complement, some unknown substance that also attached
Speaker 2: to this complex of antibody and antigen and led to
Speaker 2: all this clumping, clumping, clumping. Aerlick's conceptual idea of immunity
Speaker 2: wasn't widely recognized, like people were like, eh, I mean,
Speaker 2: I don't know. I think it goes down more like this.
Speaker 2: I think it's a little bit less of that, a
Speaker 2: little bit more of this. And one of these people
Speaker 2: was an immunologist named Carl Landsteiner, who disagreed with the
Speaker 2: one to one, highly specific and chemical nature of aerlix idea.
Speaker 2: Landsteiner felt that immunity was more individual and varied that
Speaker 2: it wasn't this binary where either very specific binding happened
Speaker 2: or it didn't, but rather that there could be degrees
Speaker 2: of specificity, and Lansteiner grew interested in a rare disease
Speaker 2: called paroximal cold hemoglobinaria. Basically, in this disease, correct me
Speaker 2: if I'm wrong. What happens is that if someone with
Speaker 2: this disease is exposed to cold temperatures, they produce an
Speaker 2: antibody that binds to a protein on the surface of
Speaker 2: their red blood cells. And then when the body gets
Speaker 2: back up to temperature, so it's like an extremity or
Speaker 2: something that complex fixes compliment and causes the red blood
Speaker 2: cells to burst open, leading to bloody urine or occasionally anemia.
Speaker 2: It's so interesting. What on Earth? I had never heard
Speaker 2: of this before. It's a thang, it's a real thing.
Speaker 2: It's wild. But this mechanism was not known at the time,
Speaker 2: of course, which is why Lansteiner was trying to figure
Speaker 2: it out. So he took some red blood cells from
Speaker 2: a few people with the disease and place them in
Speaker 2: cold water. Then he added their warm blood plasma to
Speaker 2: the tube, and when he did this, the liquid turned
Speaker 2: red as the blood cells were destroyed. Landsteiner figured that
Speaker 2: with no other substances in the tube, the antibodies in
Speaker 2: the serum must have recognized the cold red blood cells
Speaker 2: as antigens foreign substances and bound to them, which fixed
Speaker 2: a complement at warmer temperatures, rupturing the cells. These individuals'
Speaker 2: own immune systems were attacking the body's cells. This is
Speaker 2: in nineteen oh four, Landsteiner had identified one of the
Speaker 2: first autoimmune diseases. Wow. This completely went against the accepted
Speaker 2: idea more or less of antibodies only binding to foreign substances.
Speaker 2: Although Erlik did mention the possibility that autoantibodies could exist,
Speaker 2: but that there must be some sort of regulatory mechanism
Speaker 2: that prevented their existence, because it would be terrible if
Speaker 2: they if it didn't, if they were just allowed to
Speaker 2: run rampant.
Speaker 3: Whoa, And like, he's right, it does exist, but it's imperfect.
Speaker 2: I know Eric did the most. I had no idea
Speaker 2: so much. Landsteiner didn't stop at proximal cold hemoglobinuria, though
Speaker 2: he dug further into this idea of the immune system
Speaker 2: not being as specific or predictable as Erlik wanted it
Speaker 2: to be by taking a closer look at the aforementioned
Speaker 2: Wassermann test for syphilis. So this test people claimed detected
Speaker 2: antibodies specifically for the spiral keet that caused the disease.
Speaker 2: Landsteiner didn't trust this claim of specificity. I love his
Speaker 2: skepticism just throughout. I think no, no, no, no, I don't
Speaker 2: think so. And he and a few others showed that
Speaker 2: the test actually responded to various types of tissues, and
Speaker 2: that you didn't have to have syphilis to have a
Speaker 2: positive syphilis test, that in fact, the test may actually
Speaker 2: be picking up on the body's immune response to damage tissues,
Speaker 2: whether that damage was caused by syphilis or something else. Entirely,
Speaker 2: and so slowly, the idea of the immune system being
Speaker 2: more general than one to one began to take shape.
Speaker 2: The next piece of the puzzle came in the form
Speaker 2: of anaphylaxis research, which suggested that anaphylaxis was an immune
Speaker 2: response an overreaction, showing that hey, the immune system doesn't
Speaker 2: always get it right, that sometimes the immune system can
Speaker 2: actually cause severe damage to the person that it's trying
Speaker 2: to protect well, and then serum sickness where someone develops
Speaker 2: a severe reaction to antitoxins or SIRA also demonstrated the
Speaker 2: self destructive potential of the immune system. And just to
Speaker 2: show you how incomprehensible the idea of autoimmunity was, this
Speaker 2: is what two researchers involved in investigating serum sickness wrote, quote.
Speaker 2: The conception that the antibodies which should protect against the
Speaker 2: disease are also responsible for the disease sounds at first
Speaker 2: absurd end quote. One of these researchers who had this quote, Perquet,
Speaker 2: went on to coin the word and developed the concept
Speaker 2: of allergies fine, I know right. That was around nineteen
Speaker 2: o six, and it was to describe a change sensitivity
Speaker 2: of the immune system to a substance, like any kind
Speaker 2: of substance. Really, The conceptual framing of things like anaphylaxis
Speaker 2: and allergies and sensitivities as the immune system not doing
Speaker 2: what it was quote unquote supposed to and causing damage
Speaker 2: in the process paved the way for people to carry
Speaker 2: out experiments on these things, and these experiments ended up
Speaker 2: showing that the immune system could be provoked into responding
Speaker 2: so intensely to a particular stimulus that it led to
Speaker 2: severe damage or even death. In this type of research
Speaker 2: helped the idea of autoimmunity gain traction. In the early
Speaker 2: decades of the twentieth century, and so autoimmunity grew from
Speaker 2: a fringe and controversial idea of research in the early
Speaker 2: twentieth century to a popular, highly funded, and productive field
Speaker 2: unto itself by the middle of the century, helped along
Speaker 2: by the Second World War and the enormous amount of
Speaker 2: money that had been poured into biomedical research during that time.
Speaker 2: I think a quote from a book about the history
Speaker 2: of autoimmunity by Warwick Anderson and Ian McKay puts it nicely.
Speaker 2: Quote during the twentieth century, autoimmunity has progressed from a
Speaker 2: prohibited occurrence to an uncommon pathology to a normal process,
Speaker 2: from never to sometimes to always. And I just I
Speaker 2: love that because it is so much of autoimmunity as
Speaker 2: like finding the boundary between when a symptom becomes a
Speaker 2: disease and how do you do that and how do
Speaker 2: you do that in a way that is helpful and
Speaker 2: not harmful? I don't know, But in the context of lupus,
Speaker 2: this transformation from unknown pathology to autoimmunity became most apparent
Speaker 2: with the discovery of the le cell, which I mentioned earlier,
Speaker 2: but I'm going to revisit real quick. When Hargrave and
Speaker 2: colleagues discovered the cell in people with systemic lupus arithematosis,
Speaker 2: the significance of it was initially lost on them in
Speaker 2: terms of what role the cell played. All they knew
Speaker 2: was that they had watched these cells engulfing and digesting
Speaker 2: nuclear matter, probably left over from other cells. But what
Speaker 2: that meant who knew? Well. A couple of years later,
Speaker 2: other researchers would find out. These researchers showed that the
Speaker 2: production of these cells was stimulated by gamma globulin in
Speaker 2: the blood and a body, and that during a flare
Speaker 2: up of sl the a fraction of gamma globuline was high,
Speaker 2: but then dropped during clinical remission. And when they fluorescently
Speaker 2: tagged antibodies, they saw that quote, an antibody was reacting
Speaker 2: with a nuclear antigen, and so we had an antibody
Speaker 2: to a nucleic acid arising in the disease end quote.
Speaker 2: And this marked systemic lupus arithematosis as the latest disease
Speaker 2: found to have an autoimmune basis, And in some ways
Speaker 2: the post war enthusiasm for autoimmune diseases kind of mirrored
Speaker 2: that of the early years of germ theory, when behind
Speaker 2: every disease it was believed a microbe stood and now
Speaker 2: it's like every disease that we don't know has a
Speaker 2: cause is autoimmune. And that's not That's not what was
Speaker 2: found ultimately. But the research into autoimmunity uncovered the cellular
Speaker 2: basis of immune function, the interplay between innate and adaptive
Speaker 2: immune responses, and possible ways to suppress or manipulate the
Speaker 2: immune system, such as through the use of steroids. And
Speaker 2: this knowledge could be used in organ transplantation, vaccine improvement,
Speaker 2: and treatment of autoimmune diseases, where again the issue of
Speaker 2: balance came into play, striking the right treatment balance where
Speaker 2: it suppresses your immune systems enough but doesn't lead to
Speaker 2: terrible side effects, which people were noticing steroids could do.
Speaker 2: But while the concept of autoimmunity provided an answer and
Speaker 2: an avenue for treatment, there was and still is one
Speaker 2: big question that remained. Why why do some people get
Speaker 2: autoimmune diseases and others don't. Yeah, I'm not going to
Speaker 2: even pretend to try to answer that question, because no
Speaker 2: one knows, But but I do want to very briefly
Speaker 2: discuss one of the more recent interesting hypotheses that might
Speaker 2: be part of why we see the sex differences in
Speaker 2: autoimmune disorders that we see. This is called the pregnancy
Speaker 2: compensation hypothesis. Okay, so Aarin you briefly mentioned this striking
Speaker 2: sex differences in incidents of systemic lupus arithematosis. People assigned
Speaker 2: female at birth have a fourfold higher risk of developing
Speaker 2: lupus compared to those assigned male at birth, and the
Speaker 2: sex ratio for lupus is about eight to one females
Speaker 2: to males. And lupus isn't the only autoimmune disease that
Speaker 2: tends to be more prevalent in people assign female at
Speaker 2: birth compared to those assigned male at birth. Hashimotos Graves
Speaker 2: disease and multiple sclerosis also tend to follow this pattern.
Speaker 2: According to one estimate, eighty percent of all people with
Speaker 2: autoimmune conditions are female. Wow. And a lot of people
Speaker 2: are curious as to what might be driving this, And
Speaker 2: one of the latest ideas that's gotten a lot of
Speaker 2: press is the pregnancy compensation hypothesis developed by doctor Melissa
Speaker 2: Wilson and her lab at ASU and I'll include the
Speaker 2: paper as well as a couple interesting responses to this
Speaker 2: paper on our sources list for this episode, so you
Speaker 2: can get much more detailed there. But essentially, this hypothesis
Speaker 2: suggests that the stronger immune response observed in people assigned
Speaker 2: female at birth has evolved as a result of how
Speaker 2: the immune system is heavily regulated during pregnancy, predisposing females
Speaker 2: to autoimmune disorders, and that the lower numbers of pregnancies
Speaker 2: people experience in industrialized regions today, as well as fewer
Speaker 2: immune challenges in terms of pathogens and parasites and thus
Speaker 2: less immune modulation overall, has led to an increase in
Speaker 2: the rates of these disorders.
Speaker 3: So you're saying that the hypothesis is that people who
Speaker 3: are capable of pregnancy have a stronger baseline immune response
Speaker 3: because it's going to be depressed during pregnancy, and then
Speaker 3: in places where we see less pregnancies over time, we
Speaker 3: then see an increased risk of these autoimmune diseases as
Speaker 3: a result.
Speaker 2: Right, So it's sort of like the lower rates of
Speaker 2: pregnancy in some regions prevents the immune system modulation, and
Speaker 2: so then these immune systems just kind of go on
Speaker 2: overdrives on overdrive.
Speaker 3: Yeah, okay, yeah, because we do see significant declines in
Speaker 3: immune system like response and function during pregnancy.
Speaker 2: That's well known. Yeah, so okay, let's let's get into
Speaker 2: this a little bit more so. First, why would people
Speaker 2: need to have stronger immune responses to protect them during pregnancy?
Speaker 2: Keeping with the theme of this history section, it comes
Speaker 2: back to balance. Throughout pregnancy, the placenta and the pregnant
Speaker 2: person are engaged in this dance of immunomodulation. If the
Speaker 2: pregnant person's immune system is too strong, there's a risk
Speaker 2: that it recognizes the fetus as not self and then
Speaker 2: the immune system attacks it. So the placenta, which is
Speaker 2: highly invasive and like kind of can control so much
Speaker 2: is amazing currently. Yeah, so what's happening in you right now,
Speaker 2: Erin is that this highly invasive placenta kind of suppresses
Speaker 2: the maternal immune response. But then if the immune system
Speaker 2: is too suppressed, that's not good either because it leaves
Speaker 2: this person more susceptible to things like infections. And so
Speaker 2: there's this careful balance that has to be struck where
Speaker 2: the pregnant person's body has to like kind of bargain.
Speaker 2: All right, I'm going to downregulate this much. But that's
Speaker 2: my final offer, because if I get sick from a pathogen.
Speaker 2: That's not great for either of us, right, And this
Speaker 2: dance has evolved over millions of years. And to compensate
Speaker 2: for this pressure to downregulate the immune system during pregnancy,
Speaker 2: it's thought that females have evolved more heightened immune systems overall,
Speaker 2: so that when the placenta starts that immunosuppression, it doesn't
Speaker 2: drop to dire levels. In the pregnancy compensation hypothesis, this
Speaker 2: higher immune response overall in females is what drives higher
Speaker 2: predisposition to autoimmune disease. And there are some autoimmune diseases
Speaker 2: where symptoms tend to decrease during pregnancy or flare ups
Speaker 2: become more infrequent, but not all. Notably with loopus, there
Speaker 2: tends to be either no reduction in symptoms or worsening
Speaker 2: during pregnancy. Yep, again loopus. But that's the pregnancy compensation
Speaker 2: hypothesis in the tiniest of nutshells, and hopefully I portrayed it,
Speaker 2: you know, relatively accurately. But there is so much more
Speaker 2: to it, including X inactivation. So, like you talked about Aaron,
Speaker 2: people who have two X chromosomes, one X is inactivated.
Speaker 2: But it turns out this may be more incomplete or
Speaker 2: impermanent than we thought, especially in people with autoimmune diseases.
Speaker 3: We touched on that a little bit in our Turner
Speaker 3: Syndrome episode, so check that out.
Speaker 2: But yeah, you should definitely do some further reading on
Speaker 2: this because it is it is really interesting. But before
Speaker 2: I end, I do, like, I really feel like I
Speaker 2: should note that this hypothesis, while interesting and promising, is
Speaker 2: just one of many and as far as I could tell,
Speaker 2: there isn't much experimental data supporting it, and it doesn't
Speaker 2: ex everything about autoimmune diseases. No one hypothesis is going
Speaker 2: to do that because they're also different, and the authors
Speaker 2: don't claim that it does. But I have been a
Speaker 2: bit disappointed with some of the media depictions of this
Speaker 2: hypothesis because they kind of present it as like the
Speaker 2: end all be all and like here's the answer. Oh
Speaker 2: my gosh, it's so beautiful, and it's like, well, things
Speaker 2: are always more complicated than that.
Speaker 3: I think that's very normal for media depictions, which is
Speaker 3: why we will always link to primary.
Speaker 2: Yes, honestly, it never gets les annoying. But anyway, in
Speaker 2: any case, the pregnancy compensation hypothesis is a really interesting
Speaker 2: component of the overall research that's being done on how
Speaker 2: things like hormones, pathogens, the X chromosome, the placenta, pregnancy,
Speaker 2: immune responses, and all of these things kind of interact
Speaker 2: to maybe or maybe not lead to increased or decreased
Speaker 2: risk of autoimmune diseases. Well, said Eric, I just waffled
Speaker 2: a whole bunch, all right, So I think that's about
Speaker 2: as far as I want to go into the evolutionary background,
Speaker 2: just a little bit of a sampler, little taste. So
Speaker 2: allow me to wrap up extremely quickly by saying that
Speaker 2: the second half of the twentieth century was filled with
Speaker 2: refining our knowledge of systemic lupus arithmatosis research, including understanding
Speaker 2: genetic factors underlying disease development, working on better diagnostics, creating
Speaker 2: disease severity or activity indices, and finally getting a better
Speaker 2: grasp of the other more peripheral ways that lupus can
Speaker 2: affect health and quality of life. We've come a really
Speaker 2: long way, and Aaron, I'd love for you to tell
Speaker 2: me how much further we may go.
Speaker 3: Oh, I can't wait to or try to right after
Speaker 3: this break. Blah blah blah. The numbers are poor, etc.
Speaker 3: Now I'm gonna start this off.
Speaker 2: I'm gonna copy and paste this into all future episodes.
Speaker 3: Yeah, that's a good idea. It makes my job easier.
Speaker 3: But let me hit you with the numbers that I
Speaker 3: have gathered, which are predominantly from a paper that was
Speaker 3: published in twenty twenty one from Nature Reviews Roomatology that
Speaker 3: tried to look at global incidence and prevalence. And I'll
Speaker 3: mostly talk about just prevalence of loopus since it is
Speaker 3: a chronic disease. So North America prevalence of lupus estimates
Speaker 3: range large, large range from forty eight all the way
Speaker 3: up to just under four hundred cases per one hundred
Speaker 3: thousand people, Okay, And that's predominantly based on US data,
Speaker 3: which if you extrapolate using air and math, is between
Speaker 3: anywhere from one hundred and forty four thousand. That's definitely
Speaker 3: a low estimate to over a million people in North
Speaker 3: America living with loopis Okay.
Speaker 2: That's a lot.
Speaker 3: That's a lot, and it's a huge range because again
Speaker 3: not great data. In Europe, the prevalence tends to be
Speaker 3: estimated actually at substantially lower, but it also again varies
Speaker 3: really widely country to country, and not every country across
Speaker 3: the GLOS globe uses the same diagnostic criteria, which makes
Speaker 3: it even more complicated. But across Europe the estimates generally
Speaker 3: range between thirty to seventy per one hundred thousand individuals,
Speaker 3: so that's significantly lower than what we see in North America.
Speaker 3: South America we have even less studies across the continent,
Speaker 3: but estimates range from ninety to two hundred per one
Speaker 3: hundred thousand. In Asia twenty to one hundred per one
Speaker 3: hundred thousand, and then across Australasia and the African continent
Speaker 3: we have like very very limited data, and most of
Speaker 3: the data that we have is like decades and decades old.
Speaker 3: So that's what we've got. Okay, it's not it's not
Speaker 3: satisfying all the bust. One thing important to note, as
Speaker 3: we've mentioned so many times at this point, lupus across
Speaker 3: the globe affects people assigned female at birth far more often,
Speaker 3: and again, people with multiple X chromosomes are at significantly
Speaker 3: higher risk than people with a single X chromosome in general,
Speaker 3: and is usually diagnosed between the ages of fifteen to
Speaker 3: forty four, which is what we generally consider reproductive age.
Speaker 3: There are a lot of statistics, especially from the US,
Speaker 3: where we stratify a lot of our health statistics by
Speaker 3: racial and ethnic background, that show that both incidents, so
Speaker 3: number of new cases diagnosed every year, as well as
Speaker 3: overall prevalence has significant racial and ethnic disparities, with people
Speaker 3: of color being substantially more likely to be diagnosed with
Speaker 3: loopus as well as have increased risk of morbidity and
Speaker 3: mortality from lupus. And what's really important to note about
Speaker 3: this is that a these disparities exist, because that's important
Speaker 3: to know, But pretty much none of the papers that
Speaker 3: I read, except the couple that I'll link to that
Speaker 3: we're specifically looking at these disparities, offer a lot of
Speaker 3: explanation as to why these disparities exist. But it's almost
Speaker 3: certainly not due to genetic differences, because we know that
Speaker 3: race and ethnicity are not genetic basis groups, right, These
Speaker 3: are social constructs. So I think it's very easy to
Speaker 3: just leave it in a lot of these papers at
Speaker 3: the incidence and severity of disease is higher in this
Speaker 3: population than this population, and assume that that might be
Speaker 3: based on some actual physiologic difference, but most likely it
Speaker 3: is not, and it's based on a lot of really
Speaker 3: complicated factors that contribute to our overall societal health disparities.
Speaker 2: So that's important.
Speaker 3: In addition, and this I really did not know until
Speaker 3: searching this, the mortality attributed to lupus is actually very substantial.
Speaker 3: I don't have great numbers on this, though. The World
Speaker 3: Health Organization has some estimates on like age standardized mortality
Speaker 3: rates across the globe, but they're, you know, very rough estimates.
Speaker 3: But lupus is often in many countries one of the
Speaker 3: leading causes of death, like the top ten or top
Speaker 3: twenty leading causes of death four females age fifteen to
Speaker 3: forty four.
Speaker 2: Whoa.
Speaker 3: Yeah, and the probability of survival has increased significantly over
Speaker 3: the years because of improvements in treatment, but we do
Speaker 3: still see an overall increased risk of early mortality associated
Speaker 3: with lupus, which is terrifying.
Speaker 2: Mm hmm. So where are we going from here? Yeah?
Speaker 3: You mentioned aarin that there's been a lot of momentum
Speaker 3: and a lot of.
Speaker 2: Movement, and there is.
Speaker 3: Unfortunately, so far, it hasn't resulted in a ton of new.
Speaker 2: Specific treatments for lupus.
Speaker 3: While we have seen big changes in kind of using
Speaker 3: medications that are maybe used for a lot of different
Speaker 3: things and targeting them to loopus all of those different
Speaker 3: medicines that are involved in amunosuppression or immunomodulation. One of
Speaker 3: the big things I think that people are researching on
Speaker 3: now for a lot of autoimmune diseases, including lupus, are
Speaker 3: to try and get more specific, targeted treatments rather than
Speaker 3: something that's going to blanket immunosuppress entirely and therefore leave
Speaker 3: you at increased risk for infection. Okay, so there has
Speaker 3: only been one new medication that's been approved specifically for
Speaker 3: lupus in the last fifty years, and that's the biologic
Speaker 3: that I mentioned earlier.
Speaker 2: Belim mumab. I think I said it right this time.
Speaker 3: But there are currently a whole host of other medications
Speaker 3: and biologics undergoing clinical trials at like every various stage
Speaker 3: of clinical trial. Many of them are these biologics that
Speaker 3: target different aspects, but very specific aspects of our immune
Speaker 3: system in the hopes that that might help.
Speaker 2: At least some people with some types of lupus.
Speaker 3: There have been some that are promising, but nothing that's
Speaker 3: been you know, groundbreaking as of yet, and everything seems
Speaker 3: to be fairly early in the trial periods. Yeah, and then,
Speaker 3: like you mentioned, Aaron, there's also been so much work
Speaker 3: being done to really try and understand a lot of
Speaker 3: the genetic underpinnings of lupus, because not only is that
Speaker 3: going to give us more potential targets for therapies, but
Speaker 3: also maybe allow us to distinguish is this all one
Speaker 3: disease or are there a lot of specific ones underneath
Speaker 3: this big umbrella?
Speaker 2: Right? Big question.
Speaker 3: Yeah, it's a big question. But I think that's where
Speaker 3: we'll go from here. So that's systemic lupus rith amatosis
Speaker 3: aka lupus.
Speaker 2: It bears repeating. What a huge topic.
Speaker 3: Yeah, but hopefully hopefully everyone got at least something out
Speaker 3: of this.
Speaker 2: I know I did. I learned a lot. Yeah. Same absolutely,
Speaker 2: And if you where you can learn more our sources,
Speaker 2: I have several I'm going to shout out just a couple.
Speaker 2: For the history of autoimmunity, I read a book called
Speaker 2: Intolerant Bodies by Warwick Anderson and Ian McKay, and then
Speaker 2: the history of lupus I got from several papers, including
Speaker 2: one by Norman from twenty sixteen. I have a bunch
Speaker 2: more papers, including one where I totally forgot to mention
Speaker 2: that covers whether or not Jane Austen may have had lupus.
Speaker 2: What did you also know that Beethoven may have had lupus?
Speaker 3: I feel like Beethoven has had every disease that we've
Speaker 3: covered on this podcast, like that comes up a lot.
Speaker 2: He could be the first hand account for every single one.
Speaker 2: That's funny. But yeah, I have a bunch more and
Speaker 2: I'll post them.
Speaker 3: I have, yeah, quite a number of papers for this episode. Unsurprisingly,
Speaker 3: the two that I think cover just the general aspects
Speaker 3: of the biology the best if you'd like to read
Speaker 3: those are one from Annals of the Rheumatic Diseases in
Speaker 3: twenty twenty one and another from the Lancet twenty nineteen.
Speaker 3: Those two will be kind of at the top of
Speaker 3: the list. And then I also wanted to give a
Speaker 3: shout out to a book that was recommended by Sarah.
Speaker 3: Sarah who provided our first hand account, and he's one
Speaker 3: of our really good friends. She recommended this book, called
Speaker 3: the Lupus Encyclopedia, A Comprehensive Guide for p and families.
Speaker 3: It is a massive tome, but It's also available free
Speaker 3: online and I found it really useful for plain language
Speaker 3: descriptions that are very accurate and actually easy to understand
Speaker 3: because some of these papers they're rough. We will post
Speaker 3: all of our sources from this episode and every one
Speaker 3: of all episodes on our website this podcast will Kill
Speaker 3: You dot com under the episodes tap. We say that
Speaker 3: every time. I hope that you read them too.
Speaker 2: Well. A huge, huge thank you again to Sarah for
Speaker 2: taking the time to share your story and being willing
Speaker 2: to share your story, and for chatting with us.
Speaker 3: And making like air hearts but no one can see them. Yeah,
Speaker 3: air hearts their hearts. Thank you also to Bloodmobile for
Speaker 3: providing the music for this episode and all of our episodes.
Speaker 2: And thank you to Leana Squalacci for the audio mixing.
Speaker 2: We love it, We love it. Thank you to Exactly
Speaker 2: Right Network, and thank you to you listeners. We hope
Speaker 2: you liked this massive, really long, really action packed episode.
Speaker 2: I hope so too.
Speaker 3: And a special shout out to our patrons as always,
Speaker 3: thank you so much for your support.
Speaker 2: It means the world, It does all right. Well, until
Speaker 2: next time, wash your hands, you filthy animals.