The Crossroads of Autoinflammation and Autoimmunity Save
Dr. Andrea Fava shares his perspectives on autoinflammation and autoimmunity at Eular 2024 in Vienna, Austria.
Transcription
Hi everyone. My name is Andrea Fava. I'm a rheumatologist at Johns Hopkins, and I'm coming at you from, beautiful Vienna here at Hewler, where I've just listened this morning to a very fascinating session that was titled, Auto inflammation at the Crossroad of, actually, or the Crossroad of Auto Inflammation and Autoimmunity, Auto what? So, auto inflammation has been, very dear to my heart. I am a lupus specialist and yes, we think of lupus as a quintessential autoimmune disease, but, when we treat patients, there are many manifestations that truly are borrowed from, the manifestation that we see in auto inflammatory conditions.
We see all of this interferon. And then if you, several years ago, we discovered this interferonopathies, which is a group of diseases that are driven usually by a monogenic defect that lead to an excessive expression of interferon with features that partially overlap with lupus, but many that are unique. And so lupus to me, it's really this kind of mixed, group of molecularly diverse and clinically diverse diseases. And sometimes I see my clinic features that match with what we think is autoimmunity, other manifestations that are more auto inflammatory, but this concept is expanding, to all other rheumatic autoimmune condition that we treat in our clinic called rheumatic inflammatory condition. And so this morning, this was this session in which they try to break it down, to focus on what are the features that we know about auto inflammatory conditions and what are the features that we know that are more typical of, autoimmune conditions?
And then how about the mixed type in the middle? So let me just give you a couple of definitions. Auto inflammations are diseases in which there is an excessive activation of the innate immune system, whereas autoimmune diseases are those where there is an excessive or an abnormal activation of the adaptive immune system. And by adaptive, we mean the immune system where there is memory. So for example, you get a virus and then you get antibodies and you get T and B cells against this virus, and so we don't get the virus again.
And so you can think about that, for example, when we have autoimmunity, like such as autoimmune thyroid disease, where there are antibodies that are targeting one organ that can be directly pathogenic. Whereas auto inflammation, think about, familiar Mediterranean fever where there are like bouts of fevers that are abrupt, and at the molecular level, they're not triggered by a given antigen necessarily, but they're just in excessive response to non specific stimuli. Gout is in that category. Mean, we know that it's coming as a response to uric acid, but this uric acid just triggers the macrophage and the neutrophil and the immune system just to react to something bad and they release a lot of interleukin-one and they cause a lot of this bad inflammation. Anyway, so these are the features of both inflammatory diseases with rapid onset fever.
There are many, many of those, like they have interferonopathies, those associated with inflammasome, those associated with NF kappa B, but of the diseases that we see in our practice, there are some surprises. And so for example, we think of Still's disease or in children, we call it systemic JIA, and we think of those to be auto inflammatory condition, but it's interesting to see that actually the strongest genetic correlate is HLA. And so wait a minute, we have an inflammatory disease that is associated with HLA that mechanistically speak to antigen presentation and memory. And so there is some mix there and probably we need to understand this better. Doctor.
McGonagall showed that Takayasu is probably a CD8 driven auto inflammatory disease, is a vasculitis. There is a link to inflammatory bowel disease, neutrophilic dermatosis. There's a lot of features suggesting this, inflammation, coming from CD8 with the release of interferon gamma and interleukin 12, but, it's somewhere in the crossroad. He also showed some interesting data about MDA five dermatomyositis. What dermatomyositis as an auto inflammatory condition?
Well, dermatomyositis, especially MDA five is a pattern recognition, a molecule that recognizes pattern in particular, double stranded RNA, which is something that senses when we are infected with viruses and react with interfering response and an inflammatory response that we need to fight off infections. But what they noted in Yorkshire, which is in the center of The UK, they found the peak. They're not used to see these patients and they found the peak, a few years ago of a lot of patients with MDA-five like dermatomyositis without the rapidly progressive ILD that we tend to see. And they figured out that there was a very nice overlap with exposure to not so much COVID, but the COVID vaccine, With the idea that perhaps the exposure to certain nucleic acid can trigger MDA-five in some one, making it immunogenic, and they started to see this excess response and interferon with the syndrome. Something I, it was not on my radar, but something that I learned today.
But I think that looking at the crossroad, which was the presentation that came from Doctor. Shekhanachuk, that he was looking at what the diseases have a little bit of inflammation, a little bit of autoimmunity, and he made a few examples. So I'll just list them for you. One is that seropositive rheumatoid arthritis ACPA, so citrullinated antigens, well, they found these antibodies in atherosclerosis with the idea that, well, you have an antigen specific response with autoantibodies against a specific target found in the plaque and they lead to excessive interleukin production, which seems to drive eventually cardiovascular disease. So a nice interaction.
Spondyloarthritis. Yes, there is evidence of autoimmunity in spondyloarthritis with twenty percent of patients with specific antibodies mostly used in research, but there's also a very strong inflammasome activation saying, okay, we have both. We have a bit of autoimmunity and a little bit of auto inflammation. And so he showed more and more example in calling this term of MH-one apathy. Now I know that the clinicians, when we start talking about too many molecules, this can become a little bit boring, but MH-one, HLA, is a molecule that serves to, it's important to present antigens.
And in this umbrella of people who, diseases that have an association with this important molecule, there is psoriasis, spondyloarthritis, Behcet's, Still's disease. And so it seems that these diseases tend to share a lot of the pathogenic features. And so we sometimes we get trapped in this, you know, nature is complex, medicine is complex, our body is complex, our brain is simple, our mind is simple. So we simplify diseases so we can put them into boxes and so we can put a label and follow a treatment algorithm. Well, perhaps we are oversimplifying things here and these newer discoveries are helping us understanding where is the blend and perhaps we should reconsider how we understand disease.
And so the last presentation was from Ian McGinnis, beautiful presentation about, immune memory and other things. I just wanted to, quote one of his, metaphors. He brought up the concept that diseases such as lupus that we think are autoimmune and they are very heterogeneous, perhaps are kinetically diverse. What he means by that is that the disease starts at different points and then we just capture them as a snapshot. Think of seeing a marathon and just everyone starts at the same point, but then you look at where people are after twenty minutes, they are all spread out and you cannot tell from the twenty minute picture where people started at the beginning.
And so this is what we see in practice. We see disease that perhaps are very heterogeneous, but there is this different capturing time. And so we try to simplify things about understanding which cytokine comes first and explain the other so we can decide which treatment to pick. But this may be more chaotic than we think. It may be more complex.
So I think this is all very interesting and to reconsider how we think about diseases and eventually how we treat. But for now is, perhaps a little bit too early to think about this in terms of precision medicine, but probably this is how we need to think of these diseases, reconsider them, deconstruct them, reconstruct them, and hopefully we will get to procedure medicines through this pathway. Thank you very much. And to hear more about this, you can go on the RheumNow website. Thank you.
We see all of this interferon. And then if you, several years ago, we discovered this interferonopathies, which is a group of diseases that are driven usually by a monogenic defect that lead to an excessive expression of interferon with features that partially overlap with lupus, but many that are unique. And so lupus to me, it's really this kind of mixed, group of molecularly diverse and clinically diverse diseases. And sometimes I see my clinic features that match with what we think is autoimmunity, other manifestations that are more auto inflammatory, but this concept is expanding, to all other rheumatic autoimmune condition that we treat in our clinic called rheumatic inflammatory condition. And so this morning, this was this session in which they try to break it down, to focus on what are the features that we know about auto inflammatory conditions and what are the features that we know that are more typical of, autoimmune conditions?
And then how about the mixed type in the middle? So let me just give you a couple of definitions. Auto inflammations are diseases in which there is an excessive activation of the innate immune system, whereas autoimmune diseases are those where there is an excessive or an abnormal activation of the adaptive immune system. And by adaptive, we mean the immune system where there is memory. So for example, you get a virus and then you get antibodies and you get T and B cells against this virus, and so we don't get the virus again.
And so you can think about that, for example, when we have autoimmunity, like such as autoimmune thyroid disease, where there are antibodies that are targeting one organ that can be directly pathogenic. Whereas auto inflammation, think about, familiar Mediterranean fever where there are like bouts of fevers that are abrupt, and at the molecular level, they're not triggered by a given antigen necessarily, but they're just in excessive response to non specific stimuli. Gout is in that category. Mean, we know that it's coming as a response to uric acid, but this uric acid just triggers the macrophage and the neutrophil and the immune system just to react to something bad and they release a lot of interleukin-one and they cause a lot of this bad inflammation. Anyway, so these are the features of both inflammatory diseases with rapid onset fever.
There are many, many of those, like they have interferonopathies, those associated with inflammasome, those associated with NF kappa B, but of the diseases that we see in our practice, there are some surprises. And so for example, we think of Still's disease or in children, we call it systemic JIA, and we think of those to be auto inflammatory condition, but it's interesting to see that actually the strongest genetic correlate is HLA. And so wait a minute, we have an inflammatory disease that is associated with HLA that mechanistically speak to antigen presentation and memory. And so there is some mix there and probably we need to understand this better. Doctor.
McGonagall showed that Takayasu is probably a CD8 driven auto inflammatory disease, is a vasculitis. There is a link to inflammatory bowel disease, neutrophilic dermatosis. There's a lot of features suggesting this, inflammation, coming from CD8 with the release of interferon gamma and interleukin 12, but, it's somewhere in the crossroad. He also showed some interesting data about MDA five dermatomyositis. What dermatomyositis as an auto inflammatory condition?
Well, dermatomyositis, especially MDA five is a pattern recognition, a molecule that recognizes pattern in particular, double stranded RNA, which is something that senses when we are infected with viruses and react with interfering response and an inflammatory response that we need to fight off infections. But what they noted in Yorkshire, which is in the center of The UK, they found the peak. They're not used to see these patients and they found the peak, a few years ago of a lot of patients with MDA-five like dermatomyositis without the rapidly progressive ILD that we tend to see. And they figured out that there was a very nice overlap with exposure to not so much COVID, but the COVID vaccine, With the idea that perhaps the exposure to certain nucleic acid can trigger MDA-five in some one, making it immunogenic, and they started to see this excess response and interferon with the syndrome. Something I, it was not on my radar, but something that I learned today.
But I think that looking at the crossroad, which was the presentation that came from Doctor. Shekhanachuk, that he was looking at what the diseases have a little bit of inflammation, a little bit of autoimmunity, and he made a few examples. So I'll just list them for you. One is that seropositive rheumatoid arthritis ACPA, so citrullinated antigens, well, they found these antibodies in atherosclerosis with the idea that, well, you have an antigen specific response with autoantibodies against a specific target found in the plaque and they lead to excessive interleukin production, which seems to drive eventually cardiovascular disease. So a nice interaction.
Spondyloarthritis. Yes, there is evidence of autoimmunity in spondyloarthritis with twenty percent of patients with specific antibodies mostly used in research, but there's also a very strong inflammasome activation saying, okay, we have both. We have a bit of autoimmunity and a little bit of auto inflammation. And so he showed more and more example in calling this term of MH-one apathy. Now I know that the clinicians, when we start talking about too many molecules, this can become a little bit boring, but MH-one, HLA, is a molecule that serves to, it's important to present antigens.
And in this umbrella of people who, diseases that have an association with this important molecule, there is psoriasis, spondyloarthritis, Behcet's, Still's disease. And so it seems that these diseases tend to share a lot of the pathogenic features. And so we sometimes we get trapped in this, you know, nature is complex, medicine is complex, our body is complex, our brain is simple, our mind is simple. So we simplify diseases so we can put them into boxes and so we can put a label and follow a treatment algorithm. Well, perhaps we are oversimplifying things here and these newer discoveries are helping us understanding where is the blend and perhaps we should reconsider how we understand disease.
And so the last presentation was from Ian McGinnis, beautiful presentation about, immune memory and other things. I just wanted to, quote one of his, metaphors. He brought up the concept that diseases such as lupus that we think are autoimmune and they are very heterogeneous, perhaps are kinetically diverse. What he means by that is that the disease starts at different points and then we just capture them as a snapshot. Think of seeing a marathon and just everyone starts at the same point, but then you look at where people are after twenty minutes, they are all spread out and you cannot tell from the twenty minute picture where people started at the beginning.
And so this is what we see in practice. We see disease that perhaps are very heterogeneous, but there is this different capturing time. And so we try to simplify things about understanding which cytokine comes first and explain the other so we can decide which treatment to pick. But this may be more chaotic than we think. It may be more complex.
So I think this is all very interesting and to reconsider how we think about diseases and eventually how we treat. But for now is, perhaps a little bit too early to think about this in terms of precision medicine, but probably this is how we need to think of these diseases, reconsider them, deconstruct them, reconstruct them, and hopefully we will get to procedure medicines through this pathway. Thank you very much. And to hear more about this, you can go on the RheumNow website. Thank you.
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