TNR Grand Rounds - IL - 6 In Health And Disease Save
Grand Rounds Presentation by Dr. Len Calabrese
Transcription
Hello, everyone. Welcome to Tuesday night rheumatology, our grand round series. Today we're fortunate to have Doctor. Len Calabrese from the Cleveland Clinic talking about IL six in health and disease. Good evening, Doctor.
Calabrese.
This is to your health.
There you go. Wine the Rheumatologist. He made us famous on RheumNow. Who believes in the wine? Thank you for that.
So Lenny's been my guru on a lot of hot topics in the last month. Done some really good videos for us. I encourage you to look at that. Before we get into your grand rounds presentation today, Len, I wanna ask you about some of the recent data on hydroxychloroquine. Obviously for over a month now, it's been like top bullet in the news advocated by the president.
But yet the data hasn't been all that good. A lot of reasons why we're using hydroxychloroquine but we've got a slew of either neutral or negative results not really doing seroconversion as much as you'd like, or certainly not any better than not being treated with hydroxychloroquine. And then some of these reports about either more deaths or more cardiac outcomes. So the JAMA article by Borba talking, it's called the
chlor
I don't remember now it's basically a hydroxy. It's not hydroxychloroquine. It's chloroquine given in either a high dose or a usual dose. And they found that the high dose patients had more QT QTC prolongation and more deaths. Again, the thing about that study was it was prematurely halted because of the deaths that were seen.
I guess the question is, is this a fortuitous thing for rheumatologists and that maybe the negative news about chloroquine will stop the wasting of the drug in people where it may not work or should we still hold some hope for hydroxychloroquine treating COVID patients?
I mean, it's a very good question. I don't have a simple answer but my view of it is that we haven't seen the right study done to either give it thumbs up or thumbs down. You know the rationale well of why it could be effective. I don't see any use for it even empirically with other compounds that have bad drug drug interactions like azithromycin. And as many of these studies which have shown no effect make as little sense as some of the studies that have been positive.
So, the University of Minnesota studies are well designed, well powered that are gonna look both as prophylaxis which I'm not as enthusiastic about and early intervention And so I say, you know, the data will be the data.
And the good news is, I was talking to Kevin recently, he's amazed as many of us are at how fast these studies are done and how fast they're getting to print. It's amazing.
It's unbelievable, unbelievable. I'm on several DMCs for big studies that, I mean, they're virtually almost all enrolled. Just down to their last few.
So the good news is just hang in there and maybe we'll know more soon. You know, in the video that, we did at the opening of the crisis with you and Cassie, we talked about a number of issues and you brought up, I think the very, important point that I think just people are starting to get ahold of now. And that is these drugs that are especially the rheumatic disease drugs, whether it's chloroquine, hydroxychloroquine, baricitin, the IL-six inhibitors, IL-one inhibitors, etc, colchicine. The issue may not be as much as, do they work or not or is there a rationale for them as much as when they're used and sequencing and timing. Do you wanna explain your thoughts about that and tell me if you have any new thoughts about
Yeah. I mean, I think that people are buying into this as a model, that there is an early stage of triggering of innate immunity, with viral acquisition and intense viral proliferation followed by receding viral loads and the development of adaptive immunity, like antibodies, cytotoxic lymphocytes. And in the vast majority of people, it goes along and you get rid of this. But in a small percentage of young healthy people and then unfriendly large percentage of people who are older and with co morbidities, there is a lot of collateral damage, a lot of pyroptosis and then this cytokine release phenotype. And so drugs that may be good at the beginning like remdesivir probably will have little activity at the late stages and drugs like the 100 immune based therapies that are being tried in late stage may be disastrous at early stage because they may, foreshorten or inhibit the development of robust adaptive immunity.
So that I think that that model is good. Where we have made little progress Jack is in finding reliable biomarkers that actually try for Kate this. Mean, kinda you know it when you see it, but you know you'd like to intervene not too late, not too early. So I think we're getting there. You know, we've got single cell, you know, flow and all kinds of sophisticated stuff coming down the pike, but I think it's a great model.
So you hinted at the problem later in the phase where or maybe one of the last phase that there's the bad phase of, of, cytokine storm, cytokine excess, often associated with, the pulmonary and CNS demise and cytopenias. And that whole picture that looks, it's now called cytokine storm, is macrophage activation, it's hemophagocytic syndrome. And everyone's talking IL-six, IL-six, IL-six, but that Would that be your preferred target or what else should we be targeting there?
Yeah, I sent out a Twitter poll today. So obviously 90% of people's preferred target. But I have equipoise there. I think there's a lot of interesting targets and if you look at the biology, you know, TNF, IL-one, IL-six, IL-seven, GM CSF, a slew of chemokines. Interferon which is defective early in phase one of disease, very nice work by Benjamin Terrier and several other groups, but in late stages a very exorbitant and exuberant interferon response.
So, you know, there are trials of every one of those going attractive, but you know, I have equipoise and I would accommodate a number of those studies and I would let people be enrolled. I mean, don't know, I don't have the secret ballot.
Well, I'm gonna jump off screen and let you take over, the presentation and tell the audience why you've gotten interested in this and, where you think we should be going.
Fabulous. Well, I've been interested in IL-six for at least fifteen years and as most of us who've been around for a while, this came to us in the context of being a critical cytokine and rheumatoid arthritis. And at that time most of us were very unfamiliar with diseases like multicentric Castleman's disease. We had yet to even know what cytokine release syndrome was and there were no CAR T cells and who would imagine it would be used in vasculitis and who cared about neuromyelitis optica. So, you know, it's a cytokine that is in center stage.
It's feeling the heat of the limelight right now. And I think that most of us think about it as a compartmentalized biologic phenomenon. So I think it's really incredibly opportune to talk about it, what we know about it in health and disease. So, I really appreciate the opportunity Jack and everybody can see our new logo for the Fazenmeyer Center at the Cleveland Clinic. I'm a big da Vinci guy and the macrocosm and the microcosm right in the middle of the immunologic synapse.
So let's take it away. So first big shout out. This article just came out in the last week or two. I already sent an email to Ernie Choi telling what a beautiful narrative review of the history of IL-six. So this actually came out after Jack and I had agreed on this topic.
And you can see from the senior author of this, Professor Kishimoto, who is really the guy that discovered this. So, let me walk you through a little bit of a story of IL-six biology and you can go back to this article and read it at your leisure, but you know back in the 70s we were just starting to understand cytokine biology And you know, people were just starting to understand the relationship between T cells and B cells, that T cells actually provided help to B cells. People like Harvey Kleiman had done work and demonstrated there probably secreted factors And Kishimoto linked onto this. And he found that there is a factor secreted by T cells that could stimulate B cells to make immunoglobulin. And he called it B cell differentiating factor type two.
You know, a few years later as we entered the dawn of protein chemistry, it was sequenced and cloned and named IL-six. Well, other people were studying other phenomena, things to activate T cells. Take a half of a liver of a rat and ten days later it grows back because of a growth factor that turns out to be IL6. And then there were bone factors, osteoclast inducing factor, all IL-six. We now know that it belongs to a broad family of cytokines that share certain homologous signaling mechanisms that we'll talk about.
So, great paper, go to it. When we say master player, we often use the word pleomorphic and I think the thing to think about for IL-six is that you know it is produced by this wide array of both hematopoietic and viscerosomatic cells. I'm showing you this cartoon on the top and furthermore it leads to signaling within this remarkable array of hematopoietic, all our cells of innate adaptive immunity, and visceral somatic cells. So, it really is a pivot point between immunity and the body as a whole in so many different biologic processes. Now much has been made out of the signaling pathway of IL-six and my good friend and collaborator, Stefan Rosejohn, who has contributed so mightily to our understanding of this.
This is from a paper that we put out in about 2014. The bottom line is twofold. Number one, very few cells express the IL-six receptor hematopoietic cells, hepatocytes, perhaps some bowel cells, yet we know that it can lead to signaling in virtually any nucleated mammalian cell. The reason is that the IL-six receptor is solubilized. We all know this now.
IL-six binds to that soluble receptor and then it lights to the surface of a cell that expresses a molecule called GP130 which is widely expressed. And in contradistinction to the IL-six receptor bearing cells, which we call cis signaling, this is called trans signaling. So this is the pathway. Now, you think of other cytokines that we're so familiar with, TNF, when we shed a TNF receptor, it actually serves as a buffer against TNF signaling, but IL-six receptor actually facilitates signaling. There's yet a third type of signaling called trans presentation that we don't understand the biology and I don't have time to talk about it tonight.
But why do we need two pathways? I mean, everything in immunology is poetry. And you don't have to be a molecular biologist to ask the right questions. You know, why do we need cis and trans signaling? Well, before I answer that in a teleologic way, let me point out because I've just been in the middle of a lot of conversations with a lot of smart people at our place talking about IL-six levels and they don't understand the IL-six levels and should we be using it as a biomarker.
IL-six circulates in very scant amounts, one to five picograms per ml, 10 to the minus 12. Yet the soluble receptor circulates in 40 to 60 nanograms per ml, three log phases greater. So it serves as a buffer, can sop it up. Soluble GP130, that signaling protein, is even greater. So, there's this inherent buffer system which IL-six has to exceed before you see any type of biologic activity.
Now, the immune system is, you know, beautiful and poetic as I like to say, and this figure on the left shows that in homeostatic terms, there's a balance between these effector pathways on the right. Effector T and B cells being activated by upstream innate activation pathways. And then this elaboration of inflammatory cytokines of which IL-six is in the middle. And then on the left we have these tolerance and regulatory factors everything from Tregs and Bregs and regulatory dendritic cells, etc. And suppressor cytokines.
When there is perturbation of this relationship, we drive inflammation. In things like cytokine release that we'll talk about, it is fulminant and fatal, but more commonly it's low grade. And IL-six can mediate, as I will show you, both the chronic low grade inflammatory pathways and the acute and the fulminant pathways. On the right, we show a canonical evolution of T cells. T cells emigrate from the thymus as naive cells.
Display CD4 or CD8, but those CD4 cells then can be polarized in cytokine milieu to do the bidding of the immune system. If there's danger, the dendritic cell tells them what the danger signal is, where it's at, what's the nature of it, how to get rid of it and kill it. IL-six is a big driver of T cell differentiation, particularly for the Th17 pathway, and it's also a suppressor of T regulatory function. So, it tilts those scales towards inflammation. I think everyone can appreciate that as this is shown in this cartoon.
Now, last thing I wanted to mention is that why do we need cis and trans signaling? Cis signaling expressed by these few cells of hematopoietic and hepatic origin is probably a physiologic regulator. Trans signaling is probably a stress pathway and hence the ideal drug in some people's minds would be to suppress trans signaling and to leave cis signaling alone. We don't have drugs in our field that could do that right now, but people are working on them. This is one of the most important papers of 2019.
This came out December 6, Urban the first author. I've talked to Jack about this on several occasions. This is a narrative review by some of the most outstanding basic clinical and translational immunologists in the world. As you can see, several rheumatologists contributing to this as well. And what this article basically proposed is that we are in an epidemic of chronic low grade inflammatory disease that accounts for sixty percent of all mortality.
Patients with low grade patients, people with low grade inflammation have higher rates of type two diabetes, accelerated cardiovascular disease, metabolic syndrome, fatty liver, also contributes to a lot of immune mediated diseases and probably neurodegenerative diseases as well. We have biomarkers for this. CRP, as you know, a reliable and downstream molecule from the IL-six pathway is correlated with a number of comorbidities and we're now seeing this in the COVID era, that all of those diseases, all of those, and hypertension to that, chronic renal disease, all characterized by low grade inflammatory disease, are very bad for patients who acquire COVID-nineteen disease. As we think about IL-six and health and disease, we're rheumatologists. We know what inflammation is, and we know that on an evolutionary basis this process has been conserved.
When we have acute injury, we need inflammation followed by repair. This is physiologic. Normal inflammation is self limited and the whole story of resolvins flows from this. But when inflammation is chronic and unbridled, even when it is low grade, this sterile state of low grade inflammation leads to breakdown of tolerance and over time leads to end organ damage, particularly endothelial damage, and may contribute to autoimmunity, certainly contributes to things such as measurable biomarkers like poor response to vaccines and lowered resistance to infection. Know, it is driving me crazy.
I'm sure it's driving most of you crazy that if you go on social media or you go online, you know, wants to sell somebody something, you know, take a pill and boost your immune system. You know, you can boost your immune system, but you have to do it the old fashioned way through behavioral change. There's no quick fixes for this. So, we are trying to attenuate this and move on. So, inflammation, here's the picture showing, you know, danger signals coming.
These are internal danger signals. As you can see everything from uric acid to the products of pyroptosis that, you know, we can't take the garbage out generates a chronic low grade inflammatory signal, which inhibits healthy immune responses may perturb angiogenesis, alter proliferation, autophagy, all leading to this epidemic of chronic low grade inflammation. Infections can drive this but for the most part this is sterile inflammation and on the right I show, you know, the latest thinking that brain and immune system are one organ. The immune system has been referred to and I love to think of it as the brain's seventh sense. And that when we have chronic social disruption, chronic psychosocial stress like most of us are having right now, those pathways of acute inflammation are co opted and that leads to perturbation of inflammatory pathways, dysautonomia, we all know that you know immunautonomics is the hot topic right now.
And the generation of chronic low grade inflammation, glucocorticoid resistance, contributes to this phenomena. So, systemic chronic inflammation and disease, I've given you the diseases that are out there. I don't have to convince you that CRP is an important biomarker. We have proof of concept trials that even though IL-six, IL-one inhibition did not make it to regulatory approval, it lowers the risk of MI death and even reduces the rate of cancer. So, it's a proof of concept.
Methotrexate was not effective doesn't mean that the concept that chronic low grade inflammation drives this. And then we know that TNF inhibitors and actually good DMARR therapy lowers cardiovascular risks and can partially reverse insulin resistance and RA and that biomarkers including CRP correlate with much mortality in the general population. My final slide on this is the term that I love. I love the exposome. It's the measure of all exposures of an individual over a lifetime and how these exposures relate to health.
Of course, I think in terms of the immunologic exposome. You know, how we eat, how we sleep, how we exercise, how we de stress. All of this affects our inflammatory pathways and there is copious evidence from well designed trials that Mediterranean or paleo diets can lower inflammatory markers and promote health versus the standard American diet or the SAD diet with imprudent and bad fats at the other end. We know that moderate to vigorous physical exercise can drive down inflammatory markers may be partially mediated through weight loss and epidemiologically lowers the risk for respiratory infections. We know that poor sleep inhibits vaccine response and correlated with all cause mortality.
And finally, we know that chronic stress and social disruption is associated with a transcriptomic profile that has been called the conserved transcriptional response to adversity and shows up regulation of NF kappa B pathways. I posted a monograph called How to Train and Maintain Your Immune System that we give to every single patient in our clinical immunology center, which gives a no baloney, no hoax, no, you know, bug nutty, eat this berry and be healthy approach to health and tells people about eating real food, eating mostly plant based, exercising moderately, how to get there, how to use cognitive behavioral approach to sleep restoration, and most importantly, how to adopt a stepwise program to mindfulness meditation. So go to RheumNow, you can download this. We give it away for free. Print it up, use it all that you want to and be our guest.
The fact that IL-six is involved in these pathways in health and disease, as I'm pointing out, is so important for us. We know that IL-six augments pain. And why? Nerves can be activated by IL-six signaling via trans signaling and it actually lowers the threshold for activation. This has been shown in preclinical models and actually clinical models.
When you perturb people's sleep the beginning of the night, the AM circadian peak of IL-six increases, and people like Michael Irwin at UCLA has demonstrated it'll actually raise DAS scores over the near term future. And that in people with intercurrent mood disorders such as depression and chronic anxiety, multiple biomarkers are perturbed and we know that hypothalamic pituitary axis is disturbed, but the most reliable biomarker in major mood disorders is elevated IL-six both in CSF and peripheral blood. So, of these things I'm condensing and making sound bites out of a lot of science, but that's our topic to talk about this. Probably most interesting and most perplexing is the role of IL-six in energy metabolism and here I think you really get the flavor of this cis trans signaling. When we exercise, if you go out and you know burn a treadmill, get to your VO2 max, your IL-six level may go from two picograms to 70 or 100 picograms.
It can go up by, you know, nearly two log phases. Why does it do that? Well, it's very important in repair. The source of IL-six in that setting is muscle and it actually facilitates energy metabolism and glucose uptake acutely. Yet we all know that over time as we age, as we gain body mass index, CRP levels rise as do IL-six levels rise.
And over time there's an increase in insulin resistance and a trend toward adiposity with dysfunctional fat where macrophages can be polarized by IL-six. In the liver, chronic IL-six inhibits gluconeogenesis. So, is very contextual. There have been studies done with IL-six inhibitors that show that it actually can lead to partial reversal of insulin resistance. And what happens when you inhibit IL-six?
People gain weight. So, IL-six can drive central adiposity but leads to peripheral wasting just like a patient with chronic infection or cancer. And IL-six inhibition usually gains people will gain a few pounds over the ensuing six to twelve months. This was a very interesting abstract Mark Ginovace and a number of colleagues that actually demonstrated this and I was going to we'll show you this data. It's a ceruleumab study that showed that when they looked at the diabetic patients on ceruleumab with rheumatoid arthritis, regardless of the dose, that at the end of the day, fasting glucose fell, hemoglobin A1C fell almost by over a half a milligrams percent and weight gained slightly.
Trends in the non diabetics, but this is a proof of concept study that I think needs to be followed up on. This is a wonderful paper by Stefan Rohnsjohns group from Nature Reviews and Drug Discovery. And I was going to talk about it in terms of its this trans presentation. But what I will point out here as I close is that we started to think about this drug as a disease that would help rheumatoid arthritis. But, you know, over time we found that it's also very pivotal in other rheumatic diseases.
Giant cell arteritis was a pleasant surprise and it is now in my mind the standard of care where it will go in other large vessel vasculitides and PMR remains to be seen. JIA of both polyarticular and systemic variants is also very sensitive to this. And then this disease, Castleman's disease, this kind of bridging of inflammatory and neoplastic disorder, which is characterized by a good percentage of them actually being infected with a human herpes virus called HHV-eight, which encodes its own IL-six. And in these people they can have a chronic cytokine release syndrome and several IL-six inhibitors have been approved for this. In the last few years, in some countries, not all countries, IL-six inhibitor has been approved for NMO, neuromyelitis optica, a disease mediated by antibodies to the aquaporin-four ion channel.
And, you know, it comes back to the notion of why this is a B cell disease, antibody disease, this is a Rituximab disease. Well, in certain diseases, know, IL-six was initially called B cell stimulatory factor type two, and this may belie its mechanism of action. And then in 2017, with the approval of CAR T cell therapy for hematologic malignancies, which are now creating traction across the board in all types of different CAR T cells, About half of these patients develop an inflammatory syndrome that can be fatal. Emily White house, the first child to survive this, that was cured by CAR T cells, you know, would have died, but they saw a signal in cytokines that IL-six was profoundly elevated and she was rescued by this and it is now a rescue therapy for this disease. As we now go below the line, I think there's two areas of interest to us greatly.
One is in the area of treating immune related adverse events from cancer immunotherapy, particularly checkpoint therapy, where we have published a lot on this and a lot of our patients with chronic polyarthritis and chronic polymyalgia that can't get off steroids have been salvaged by this. And now there are several protocols, I don't know if I have this here, that are using IL-six in combination with checkpoint inhibitors out of the gate to see if it improves their activity and decreases their side effects. And then finally, the COVID-nineteen story that I'll come to in a minute. This is just to remind me to talk about the CAR T cell story. CAR T cells will only increase in scope and they'll increase in their lethality.
We now have what we call armored CAR T cells that do not long, don't get resistant to the tumors, And we need ways of controlling this. IL-six is very effective. It doesn't work for all patients. TNF may, anti TNF may still have a role, anti GM CSF may still have a role, and other therapies are still in therapy. This is just looking at cytokine release syndrome after these and showing the data.
You know, you don't have to be a statistician. When you see the levels, you get the levels of IL-six in these cytokine release patients, this is up five log phases. I'll point out that in patients with COVID, most of the IL-six levels are down here. Not very impressive compared to this. And then after a course of Tocilizumab, everything comes down.
Temperature, heart rate, blood pressure stabilizes, and all the biomarkers go in the right direction. So, this is our first hint that this is pretty hip stuff for cytokine release. And then finally, this is our thinking of IL-six as a preemptive target in cancer. Without having a lot of time to talk about this because I want to spend time answering questions and discussing this with Jack, know, IL-six functions through JAK STAT pathways and while several JAKs and STATs are solicited, JAK1 STAT3 seem to be more hegemonous in this activation pathway. And that there are downstream effector molecules from STAT3 that may contribute to tumorigenesis.
There are some forms of malignancy, particularly some forms of hepatoma and some forms of lung cancer where STAT3 is hyper activated and may actually drive tumorigenesis. And as I show on the bottom, this is clinicaltrials.gov study that is just getting underway where patients are given tocilizumab in combination with ipilimumab, an anti CTLA-four, and nivolumab, an anti PD-one, in patients with unresectable stage three or four melanoma. So, is how the study is being done, and it's going to be TOSI or placebo in combination with standard checkpoint therapy and the endpoints are how's the tumor do? How does the side effect profile go? Pretty amazing.
So finally, this is what Jack was asking me at the beginning. This is a brief paper. I'll do a shout out for Brian Mandel and the Cleveland Clinic Journal of Medicine. They have a curbside consult, COVID consult section where the articles are being posted by the day. Cassie has several papers up there.
I have a few. This is a figure that I put in the first edition of this. This is how we envision COVID-nineteen disease, the asymptomatic stage of viral recognition and acquisition, a triggering of PAMPs and generating inflammation and the virus establishes. We know that viral loads decrease over time. Even people dying have lower viral loads than they did initially.
Stage two, we're acquiring adaptive immunity, specific antibody and viral specific T cells and B cells. And here we start generating a more robust inflammatory response as the invaded cells die off, die off after the virus has penetrated them and they die of pyruptosis and release their products that damp receptors now pick up. And then in the unlucky small percentage develop this progressive end organ dysfunction and inflammatory syndrome that can look like a cytokine release syndrome. I do not like the language that it is HLH or it's MAS. It is not.
This is not CAR T cell cytokine release syndrome. You know, there are perturbations of cascades and networks of cytokines, but there's no reason to think that the same drugs, you know, will work equally as well in this pathway. There are different effector mechanisms that we're only starting to understand through big data, artificial intelligence, and hopefully the generation of biomarkers. Yet, when we measure cytokines here, yeah, IL-six, IL-one, TNF, IL-eight, IL-seven, all elevated. Cytokines such as GM CSF, are not normally detectable in healthy people are elevated.
Just like they're elevated in rheumatoid arthritis and synovial fluid. G CSF is elevated. You know, which are the bad actors? Interferon which is defective in stage one then becomes more abundant and maybe contributing to immunopathogenesis in stage three. So, there are now over 100 different strategies out there to parse this stage three, and we'd like to be able to treat people right here.
They've developed adaptive immunity, we won't suppress it, but they're not on a ventilator, they haven't developed ARDS, and they don't have irreversible disease. So, you know, I kept this slide just to keep it blank until like, you know, the other day, because you can find whatever you want to find in this space. There are studies being spit out of PubMed that are not even peer reviewed right now on this and take your choices. There are uncontrolled studies showing that all IL-six inhibitors have been beneficial. There are some that have shown less benefit than others.
And the question is, you know, why is this happening? Is it, you know, too advanced disease or they're using it in or is it the wrong drug? And as you everyone knows that there are now several large international RCTs that are being recruited that are almost fully recruited for both tocilizumab and ceruleumab, that we will have data in eight weeks and we won't be guessing. The next time that Jack and I talk about this, we'll have hard data on this. You know, I keep my fingers crossed.
I have equipoise that, you know, these are good targets to look at, but you know, there's other targets out there too. This is one of the this is ancient history. Wrote this way back in 04/13/2020. I think that the figure I showed you, you can go rip that off for your talks on this, but the data are different right So, these are the, you know, here's our buddies. I have a cut off Xavier.
He's standing over here. Maxine Dugados. They say that really bad is Or that tocilizumab is great, but they didn't release the data. And New York Times says that's really mad is not that they don't release the data either. Scientists.
You know, Lewis Thomas, one of my favorite all time authors and You know, National Book Award winner fifty years ago for the lives of a cell. He said, you know, in science, when science meets the public, the public is well motivated. They don't have guile, but they want to believe in things that could be hoaxes, you know. President says hydroxychloroquine sounds good to him and drinking Clorox and light sounds good. Yeah, why not?
Sounds, you know, Jason important guy, he said that. Investigators, Investigators, scientists, their makeup is that they're willing to say they're wrong when the data doesn't show it. So we have to stand up for science and hold the fort. So anybody that likes this chain of thought, please follow me on Twitter lcalabriesdl. I try to feed about what's happening in immunology, zen and fine wine and a little bit of what's going on in humanism.
So I think that's the end. Those are the diseases that we know about, but there's so much more coming down the pike. I think I'll stop and I'll kind of bug out of here.
Alright, Lynn, that was great. Thanks very much for that. I want to remind our audience that we're now going to do some q and a for the next fifteen-twenty minutes. Let's start with a few questions from the audience. So there was one comment about the Brazilian study on qtc intervals that said that the qtc intervals actually correlated with poor candidates, meaning that they were older and had more cardiovascular disease, rather than that not just the qtc, but that death in that study did not correlate with qt qt intervals prolongation, which was different, but it correlated more with poor candidates.
So again, that might be again, there's a lot of buzz around the cardiac effects, but really it seems like it's the comorbidities and the setup factors of age and obesity and cardiovascular disease and diabetes that everyone really should be worried
Well, mean, I think that there's all that, but I mean, so many of those studies are confounded by crazy drug drug interactions. And the vast majority of the studies that have shown the poorest outcomes and the most toxicity have been these hydroxychloroquine and azithromycin studies. And you know, like it's really not a hydroxychloroquine study. It's a study of hydroxychloroquine in a drug that has a serious drug drug interaction. So call it what it is.
I mean, am not worried about ten days of hydroxychloroquine monotherapy by and large in people who are not critically ill. I just don't know that it works but everybody on the other half of these studies is combining it with things like antiretroviral drugs and things like this. So it's not a study of one drug.
So, one of our, docs, Doctor. Horvath wants to know if you think there's any difference between tocilizumab and ceruleumab either I guess in what you treat or in these COVID studies, you think it makes any difference?
I can't imagine why it would be any different. I just can't. They're both highly effective drugs in the same space. They seem to work. I mean, they're both anti receptors, they both inhibit cis and trans signaling.
Their PDs are a little bit different, their PKs a little bit different. It'll be hard for me to imagine that one will be lights out and the other is going to be a negative trial. But it's not like, sorukumab that was an anti IL-six and had a different toxicity profile. But I don't know what do you think?
I kind of agree with that. I don't know that I'd have a different thought.
We'll have to wait and see. What's that? We'll have to wait and see.
Yeah, mean, think that that right now the real problem is you really can't be right or wrong right now because a lot of what's out there is bad data. One of our docs wants to know about tocilizumab and acute myocardial infarction. We talked about the search study and anakanikinumab study and where it worked and it didn't work. Would an IL-six inhibitor work in that setting? Cardiovascular patient, improving cardiac outcomes, could it work?
I don't even know what preclinical modeling is being done, but I will tell you that the Cleveland Clinic, we have a experimental protocol that if you have COVID and you have cardiac involvement by troponins, the study is using anti IL-one.
Checkpoint inhibitor induced arthritis, unresponsive to steroids and DMARDs, would you prefer to use a TNF inhibitor or an IL-six inhibitor?
Actually, at the moment, I mean, isn't like a lights out notion, but I feel that there are so many reasons to pursue anti IL-six therapy in there that Cassie and I have gravitated mostly to going to IL6 early. And there are both preclinical tumor models where anti IL-six actually enhances the anti tumoral effects of some of these therapies. So, we know that it has a decent toxicity profile there. We're experienced with it and it works very promptly. So no head to head obviously but just a comfort zone.
Wish Cassie would throw in on that shoes here.
What are your thoughts on targeting IL-seventeen in the cytokine storm?
Well, IL-seventeen, it has been examined and it is elevated. Absolutely. You know, if you look at preclinical modeling of cytokine release and you know, the oldest and simplest model is to take a mouse and expose it to LPS and then start measuring cytokines. And you know you see this you know TNF, IL-one, IL-six and then downstream, you know, this panoply of inflammatory cytokines. So when we talk about upstream cytokines, you know, IL-seventeen is downstream.
So I wouldn't expect IL-seventeen to, you know, have profound effects of turning off IL-six and IL-one and TNF unless you show me some data. Yet in maybe some end organ damage, it might be very, very, very vital. The other cytokine that nobody is enthusiastic about yet there are four clinical trials that we're talking about earlier is GM CSF which is not detectable in healthy people and is highly upregulated in the lungs of people with ARDS and other forms of advanced disease. It's the product of innate immune cells, these CD14 and CD16 activated monocytes and some people believe that it may be upstream of these other very basic inflammatory cytokines and we will know there's trials of anti GMCFS, IL-one, anti IL-six, anti interferon.
So a recent issue of Lancet, an article by Mark Feldman, Tiny Mani and others making a plea for TNF inhibitors in COVID. I mean, 3,000 words on the subject, they had a lot of good ideas. And there are a few trials of at least adalimumab and infliximab that I know of, but not as many as what we're seeing with other drugs, but do you think that that also makes some sense?
I think it absolutely makes sense. I think that, you know, look, we've been using TNF inhibitors in this IRAE world like crazy because they were available, were empirically used, you know, a lot of people are concerned about the response on, you know, the effects on host response to the virus. Yet, you know, there's no evidence whatsoever that anti TNF inhibits our clinical response to influenza. It certainly doesn't inhibit our vaccine response to influenza. All the models are, you know, knockout models, which I don't think are relevant here.
I would have equipoise to put a patient in a study of anti TNF. But as you say, I don't think there's any large scale anti TNF trials going on right now.
Do you think our patients, because we have so many patients taking drugs that target these molecules, might that be a reason why we're seeing so little COVID or so little bad COVID in our patients? A recent MMWR report of three zero eight COVID infected people in Georgia looked at the comorbidity relationships. A quarter of the patients had no comorbidity. And then the usual ones played out obesity, heart disease, etcetera. At the bottom of the list, one to two percent had a rheumatologic immunologic disease where the elderly, like 50, 60 year old having a five percent representation.
I think there's some evidence, I think it's partly because our patients are on these agents and their disease is well controlled. What do you think?
I mean, we've had some anecdotes of that of patients with very peculiar clinical courses to COVID-nineteen. At the minimum, I would say there is no smoking gun that they are overrepresented. You know, whether this all plays out, you know, let's look at the COVID RheumAlliance, you know, eight weeks from now dispassionately and see if we can get a little bit better handle on this. But so far, you know, I kind of like, you know, got my fingers crossed that your observation is accurate and we'll see.
Evan Leibowitz says that in his ICU and hospital, most of the COVID patients are overweight or obese. Is that a role for adipokines as a risk factor here or what do you think underlies the obesity risk factor issue?
I think that the common denominator of all these things, to me, is my hypothesis, is that it's a state of endothelial health. Every one of these comorbidities, whether it's type two diabetes or hypertension and obesity and chronic low grade inflammation, you know, contributes and cardiac disease, course, metabolic syndrome to accelerated morbidity and mortality. And whether that is because those cells are vulnerable to infection and there's already evidence that endothelial cells can be directly infected, whether it makes them vulnerable to complement mediated activation and a procoagulant effect. And as you know, that patients with COVID have hyperthrombotic disease, both gross clots and, you know, D dimers and clotting pathways. I think that is the smoking gun.
A beautiful paper ten days ago by Jeffrey Lawrence and group showing that endothelial cells can be activated and damaged by complement being activated by COVID via lectin pathway. Everything that you have sick endothelial cells, those are patients that get hammered. And that's what happens when you get old.
David Knapp asked a question about patients who are not severely affected or asymptomatic. It's supposedly eighty plus percent and there's a fifteen percent that seem to progress get respiratory symptoms and then subset of those who get really bad. But that's in that middle phase that you gave in that graph, but there are you put it you point out one line when in fact there are two divergent lines, with most people sort of having adaptive immune response that seems to work. And then there's others where it is insufficient or maybe there's an excess of an innate signal. What do you think is going on?
And how do we differentiate?
I do not think that people I don't think there's much evidence that people are dying of overwhelming viral infections. They are dying of collateral damage. And I do believe that this whatever you want to call it, I'd like to call it cytokine release syndrome because it's indigenous to this disease. It's not MAS, HLH, CAR T, JIA, it's its own dealio using the same players. And I think that adaptive immunity helps but somehow people are unable to turn off this process.
I keep using the term pyroptosis but that is what's happening here. That's when cells don't die, you know, neatly and quietly, they explode. And all of that, those damps and alarmins are setting off this pathway. If you look at the lung pathology, I've learned so much about this from talking to these lung pathologists and critical care guys, this is pretty unique. You know, only a small fraction of them get ARDS pathologically.
This is something different. I mean, you know, you got activated macrophages, got a lot of, you know, alveolar damage, but they don't all have hyaline membranes. This is something unique. The trick will be is that no one can magically draw that line. I was talking to some of the top pulmonologists in the world today about this on a conference call.
You know, when does the patient declare himself as headed for the ventilator? You know it six hours beforehand, but you don't know it two days or seventy two hours beforehand. You know, the oxygen goes up, these people have these resilient lungs, you know, are highly compliant. We don't have biomarkers for that, no.
So given that a lot of the damage is what accounts for the death and bad outcomes, should rheumatologists be playing a bigger role in managing COVID patients? I mean, all these drugs we're talking about are ones that we're good at.
Well, I think and I'm sure at your place is the same that any place that is doing clinical trials in COVID needs to have people like us, know, mano a mano, working on these protocols. And Cassie's on a number of them. I've consulted and Brian Mandel has consulted to virtually all the decision making. You know, they do need our help. You know, it's not that we're smart and they're dumb, in our sandbox with our drugs just like IRAE's.
So, I think this is an incredible interprofessional disease. You know, I said, you know, kind of fancy ourselves at the clinic as being at this nexus of room and ID. I said, you know, of all the gin joints in all the world, COVID-nineteen walked into ours. You know, this is this is what we do for a living here. So, we're very proud to contribute and we're very humble to learn from these guys.
You know, I've learned more critical care medicine now than I ever knew.
Herb Barath asked about the JAK inhibitors and their role in this syndrome and can they compete with the IL-six inhibitors, especially at that end stage there?
I do not you know I have been looking at this. I'd love to get your take on this and you know the modeling of this is very very different than the cytokine inhibition. You know, the first data was generated by, you know, machine learning that showed that, you know, baricitinib and ruxolitinib and one of these other ones I never even heard of, you know, would be particularly valuable in COVID-nineteen infection because, not because it was inhibiting cytokines, it's because it inhibited viral entry. You know, there are these crazy kinases that after ACE2 binding then contribute to membrane fusion. These are molecules I've never even heard of in my life.
And so, that's interesting, but that's upstream, I think, you know, that's in the viruses proliferating. I wouldn't want to be using a drug that inhibits interferon in the middle pathway, because you need interferon for the antiviral response. I know that there are RCTs of all of these drugs going on, but I would be wanting to use them in, you know, after adaptive immunity is established. Yeah, I'm probably wrong in all of this stuff, but you have to think of like where in the in the process is the MOA working?
Doctors Kisano and Fung have asked questions about measuring IL-six. Would you do them? What does it mean?
Yeah, great question. Thank You don't need it. You don't need it to manage this disease. To clinically recognize cytokine release is relatively simple. And CRP and ferritin and D dimers and, you know, falling lymphocyte counts, all of the things that we see in other cytokine release syndromes of other nosology are effective.
I told you the IL-six levels, which we do, you know, they go up, but they don't go up by more than a couple log phases and then you give tocilizumab or ceruleumab and then they go, hey, we checked the IL-six afterwards, it's going up. Well, yeah, it is going up. So what do you want me to do about it? Like, why did we measure this? I told you not to measure this.
If there was a cutoff, I would say do it, but we don't need it.
Last question from Doctor. Zuckerman. Is there a role for anti IL-six therapy to moderate the prothrombotic effects seen in COVID?
You know, it very well might be effective. I mean, you know that Ian MacInnis looked at endothelial health in RA patients on Tocilizumab, didn't find dramatic effects on flow mediated dilatation, but he found a lot of ex vivo effects on endothelial health. You know, we don't understand the hypercoagulability right now. It's not DIC, but it is a hypercoagulable state and a lot of people are hot to trot on this. You know, there are also now a handful of anti complement strategies in RCTs.
That may be a link between coagulation, tissue factor, endothelial health. My closing comment, Jack, is that first of all, this is so exciting to be able to talk expansively about this molecule, which there's so much to still be learned about. But I will tell you that six months from now, you know, hopefully when this thing is getting into the second half, hopefully into the fourth quarter, we will have learned so much. It never ever in our whole lifetimes would we have imagined this, you know. This took from 1981 to 1997 to learn this much about HIV that we've learned about in three months.
Right. And it's only gonna go exponential from here. I'm so grateful that, you know, I'll be here to throw my pebbles on the pile, as Sir Williams said.
Well, Len, thank you so much for your time. We really appreciate your leadership, your education and guidance on some very difficult issues. We look to you now and in the future to help us with this. So we really appreciate your being here. I wanna end with a pitch for next week and our speaker who is gonna be Joan Merrill.
She's going to talk about, what does COVID have to do with lupus. I think that's gonna be an interesting talk to say the least. And then also, we're gonna talk about, in the weeks to come, we're gonna have lectures not just from Doctor. Merrill, but you'll see we have a lecture the following week from, from down under, Philip Robinson, one of the fellows who started the Global Rheumatology Alliance, and Peter Nash. They're gonna talk about their experience, and then the week after that's gonna be John Kay updating us on biosimilars.
Glenn, thank you so much. Have a good night.
Everybody stay safe.
Thank you.
Calabrese.
This is to your health.
There you go. Wine the Rheumatologist. He made us famous on RheumNow. Who believes in the wine? Thank you for that.
So Lenny's been my guru on a lot of hot topics in the last month. Done some really good videos for us. I encourage you to look at that. Before we get into your grand rounds presentation today, Len, I wanna ask you about some of the recent data on hydroxychloroquine. Obviously for over a month now, it's been like top bullet in the news advocated by the president.
But yet the data hasn't been all that good. A lot of reasons why we're using hydroxychloroquine but we've got a slew of either neutral or negative results not really doing seroconversion as much as you'd like, or certainly not any better than not being treated with hydroxychloroquine. And then some of these reports about either more deaths or more cardiac outcomes. So the JAMA article by Borba talking, it's called the
chlor
I don't remember now it's basically a hydroxy. It's not hydroxychloroquine. It's chloroquine given in either a high dose or a usual dose. And they found that the high dose patients had more QT QTC prolongation and more deaths. Again, the thing about that study was it was prematurely halted because of the deaths that were seen.
I guess the question is, is this a fortuitous thing for rheumatologists and that maybe the negative news about chloroquine will stop the wasting of the drug in people where it may not work or should we still hold some hope for hydroxychloroquine treating COVID patients?
I mean, it's a very good question. I don't have a simple answer but my view of it is that we haven't seen the right study done to either give it thumbs up or thumbs down. You know the rationale well of why it could be effective. I don't see any use for it even empirically with other compounds that have bad drug drug interactions like azithromycin. And as many of these studies which have shown no effect make as little sense as some of the studies that have been positive.
So, the University of Minnesota studies are well designed, well powered that are gonna look both as prophylaxis which I'm not as enthusiastic about and early intervention And so I say, you know, the data will be the data.
And the good news is, I was talking to Kevin recently, he's amazed as many of us are at how fast these studies are done and how fast they're getting to print. It's amazing.
It's unbelievable, unbelievable. I'm on several DMCs for big studies that, I mean, they're virtually almost all enrolled. Just down to their last few.
So the good news is just hang in there and maybe we'll know more soon. You know, in the video that, we did at the opening of the crisis with you and Cassie, we talked about a number of issues and you brought up, I think the very, important point that I think just people are starting to get ahold of now. And that is these drugs that are especially the rheumatic disease drugs, whether it's chloroquine, hydroxychloroquine, baricitin, the IL-six inhibitors, IL-one inhibitors, etc, colchicine. The issue may not be as much as, do they work or not or is there a rationale for them as much as when they're used and sequencing and timing. Do you wanna explain your thoughts about that and tell me if you have any new thoughts about
Yeah. I mean, I think that people are buying into this as a model, that there is an early stage of triggering of innate immunity, with viral acquisition and intense viral proliferation followed by receding viral loads and the development of adaptive immunity, like antibodies, cytotoxic lymphocytes. And in the vast majority of people, it goes along and you get rid of this. But in a small percentage of young healthy people and then unfriendly large percentage of people who are older and with co morbidities, there is a lot of collateral damage, a lot of pyroptosis and then this cytokine release phenotype. And so drugs that may be good at the beginning like remdesivir probably will have little activity at the late stages and drugs like the 100 immune based therapies that are being tried in late stage may be disastrous at early stage because they may, foreshorten or inhibit the development of robust adaptive immunity.
So that I think that that model is good. Where we have made little progress Jack is in finding reliable biomarkers that actually try for Kate this. Mean, kinda you know it when you see it, but you know you'd like to intervene not too late, not too early. So I think we're getting there. You know, we've got single cell, you know, flow and all kinds of sophisticated stuff coming down the pike, but I think it's a great model.
So you hinted at the problem later in the phase where or maybe one of the last phase that there's the bad phase of, of, cytokine storm, cytokine excess, often associated with, the pulmonary and CNS demise and cytopenias. And that whole picture that looks, it's now called cytokine storm, is macrophage activation, it's hemophagocytic syndrome. And everyone's talking IL-six, IL-six, IL-six, but that Would that be your preferred target or what else should we be targeting there?
Yeah, I sent out a Twitter poll today. So obviously 90% of people's preferred target. But I have equipoise there. I think there's a lot of interesting targets and if you look at the biology, you know, TNF, IL-one, IL-six, IL-seven, GM CSF, a slew of chemokines. Interferon which is defective early in phase one of disease, very nice work by Benjamin Terrier and several other groups, but in late stages a very exorbitant and exuberant interferon response.
So, you know, there are trials of every one of those going attractive, but you know, I have equipoise and I would accommodate a number of those studies and I would let people be enrolled. I mean, don't know, I don't have the secret ballot.
Well, I'm gonna jump off screen and let you take over, the presentation and tell the audience why you've gotten interested in this and, where you think we should be going.
Fabulous. Well, I've been interested in IL-six for at least fifteen years and as most of us who've been around for a while, this came to us in the context of being a critical cytokine and rheumatoid arthritis. And at that time most of us were very unfamiliar with diseases like multicentric Castleman's disease. We had yet to even know what cytokine release syndrome was and there were no CAR T cells and who would imagine it would be used in vasculitis and who cared about neuromyelitis optica. So, you know, it's a cytokine that is in center stage.
It's feeling the heat of the limelight right now. And I think that most of us think about it as a compartmentalized biologic phenomenon. So I think it's really incredibly opportune to talk about it, what we know about it in health and disease. So, I really appreciate the opportunity Jack and everybody can see our new logo for the Fazenmeyer Center at the Cleveland Clinic. I'm a big da Vinci guy and the macrocosm and the microcosm right in the middle of the immunologic synapse.
So let's take it away. So first big shout out. This article just came out in the last week or two. I already sent an email to Ernie Choi telling what a beautiful narrative review of the history of IL-six. So this actually came out after Jack and I had agreed on this topic.
And you can see from the senior author of this, Professor Kishimoto, who is really the guy that discovered this. So, let me walk you through a little bit of a story of IL-six biology and you can go back to this article and read it at your leisure, but you know back in the 70s we were just starting to understand cytokine biology And you know, people were just starting to understand the relationship between T cells and B cells, that T cells actually provided help to B cells. People like Harvey Kleiman had done work and demonstrated there probably secreted factors And Kishimoto linked onto this. And he found that there is a factor secreted by T cells that could stimulate B cells to make immunoglobulin. And he called it B cell differentiating factor type two.
You know, a few years later as we entered the dawn of protein chemistry, it was sequenced and cloned and named IL-six. Well, other people were studying other phenomena, things to activate T cells. Take a half of a liver of a rat and ten days later it grows back because of a growth factor that turns out to be IL6. And then there were bone factors, osteoclast inducing factor, all IL-six. We now know that it belongs to a broad family of cytokines that share certain homologous signaling mechanisms that we'll talk about.
So, great paper, go to it. When we say master player, we often use the word pleomorphic and I think the thing to think about for IL-six is that you know it is produced by this wide array of both hematopoietic and viscerosomatic cells. I'm showing you this cartoon on the top and furthermore it leads to signaling within this remarkable array of hematopoietic, all our cells of innate adaptive immunity, and visceral somatic cells. So, it really is a pivot point between immunity and the body as a whole in so many different biologic processes. Now much has been made out of the signaling pathway of IL-six and my good friend and collaborator, Stefan Rosejohn, who has contributed so mightily to our understanding of this.
This is from a paper that we put out in about 2014. The bottom line is twofold. Number one, very few cells express the IL-six receptor hematopoietic cells, hepatocytes, perhaps some bowel cells, yet we know that it can lead to signaling in virtually any nucleated mammalian cell. The reason is that the IL-six receptor is solubilized. We all know this now.
IL-six binds to that soluble receptor and then it lights to the surface of a cell that expresses a molecule called GP130 which is widely expressed. And in contradistinction to the IL-six receptor bearing cells, which we call cis signaling, this is called trans signaling. So this is the pathway. Now, you think of other cytokines that we're so familiar with, TNF, when we shed a TNF receptor, it actually serves as a buffer against TNF signaling, but IL-six receptor actually facilitates signaling. There's yet a third type of signaling called trans presentation that we don't understand the biology and I don't have time to talk about it tonight.
But why do we need two pathways? I mean, everything in immunology is poetry. And you don't have to be a molecular biologist to ask the right questions. You know, why do we need cis and trans signaling? Well, before I answer that in a teleologic way, let me point out because I've just been in the middle of a lot of conversations with a lot of smart people at our place talking about IL-six levels and they don't understand the IL-six levels and should we be using it as a biomarker.
IL-six circulates in very scant amounts, one to five picograms per ml, 10 to the minus 12. Yet the soluble receptor circulates in 40 to 60 nanograms per ml, three log phases greater. So it serves as a buffer, can sop it up. Soluble GP130, that signaling protein, is even greater. So, there's this inherent buffer system which IL-six has to exceed before you see any type of biologic activity.
Now, the immune system is, you know, beautiful and poetic as I like to say, and this figure on the left shows that in homeostatic terms, there's a balance between these effector pathways on the right. Effector T and B cells being activated by upstream innate activation pathways. And then this elaboration of inflammatory cytokines of which IL-six is in the middle. And then on the left we have these tolerance and regulatory factors everything from Tregs and Bregs and regulatory dendritic cells, etc. And suppressor cytokines.
When there is perturbation of this relationship, we drive inflammation. In things like cytokine release that we'll talk about, it is fulminant and fatal, but more commonly it's low grade. And IL-six can mediate, as I will show you, both the chronic low grade inflammatory pathways and the acute and the fulminant pathways. On the right, we show a canonical evolution of T cells. T cells emigrate from the thymus as naive cells.
Display CD4 or CD8, but those CD4 cells then can be polarized in cytokine milieu to do the bidding of the immune system. If there's danger, the dendritic cell tells them what the danger signal is, where it's at, what's the nature of it, how to get rid of it and kill it. IL-six is a big driver of T cell differentiation, particularly for the Th17 pathway, and it's also a suppressor of T regulatory function. So, it tilts those scales towards inflammation. I think everyone can appreciate that as this is shown in this cartoon.
Now, last thing I wanted to mention is that why do we need cis and trans signaling? Cis signaling expressed by these few cells of hematopoietic and hepatic origin is probably a physiologic regulator. Trans signaling is probably a stress pathway and hence the ideal drug in some people's minds would be to suppress trans signaling and to leave cis signaling alone. We don't have drugs in our field that could do that right now, but people are working on them. This is one of the most important papers of 2019.
This came out December 6, Urban the first author. I've talked to Jack about this on several occasions. This is a narrative review by some of the most outstanding basic clinical and translational immunologists in the world. As you can see, several rheumatologists contributing to this as well. And what this article basically proposed is that we are in an epidemic of chronic low grade inflammatory disease that accounts for sixty percent of all mortality.
Patients with low grade patients, people with low grade inflammation have higher rates of type two diabetes, accelerated cardiovascular disease, metabolic syndrome, fatty liver, also contributes to a lot of immune mediated diseases and probably neurodegenerative diseases as well. We have biomarkers for this. CRP, as you know, a reliable and downstream molecule from the IL-six pathway is correlated with a number of comorbidities and we're now seeing this in the COVID era, that all of those diseases, all of those, and hypertension to that, chronic renal disease, all characterized by low grade inflammatory disease, are very bad for patients who acquire COVID-nineteen disease. As we think about IL-six and health and disease, we're rheumatologists. We know what inflammation is, and we know that on an evolutionary basis this process has been conserved.
When we have acute injury, we need inflammation followed by repair. This is physiologic. Normal inflammation is self limited and the whole story of resolvins flows from this. But when inflammation is chronic and unbridled, even when it is low grade, this sterile state of low grade inflammation leads to breakdown of tolerance and over time leads to end organ damage, particularly endothelial damage, and may contribute to autoimmunity, certainly contributes to things such as measurable biomarkers like poor response to vaccines and lowered resistance to infection. Know, it is driving me crazy.
I'm sure it's driving most of you crazy that if you go on social media or you go online, you know, wants to sell somebody something, you know, take a pill and boost your immune system. You know, you can boost your immune system, but you have to do it the old fashioned way through behavioral change. There's no quick fixes for this. So, we are trying to attenuate this and move on. So, inflammation, here's the picture showing, you know, danger signals coming.
These are internal danger signals. As you can see everything from uric acid to the products of pyroptosis that, you know, we can't take the garbage out generates a chronic low grade inflammatory signal, which inhibits healthy immune responses may perturb angiogenesis, alter proliferation, autophagy, all leading to this epidemic of chronic low grade inflammation. Infections can drive this but for the most part this is sterile inflammation and on the right I show, you know, the latest thinking that brain and immune system are one organ. The immune system has been referred to and I love to think of it as the brain's seventh sense. And that when we have chronic social disruption, chronic psychosocial stress like most of us are having right now, those pathways of acute inflammation are co opted and that leads to perturbation of inflammatory pathways, dysautonomia, we all know that you know immunautonomics is the hot topic right now.
And the generation of chronic low grade inflammation, glucocorticoid resistance, contributes to this phenomena. So, systemic chronic inflammation and disease, I've given you the diseases that are out there. I don't have to convince you that CRP is an important biomarker. We have proof of concept trials that even though IL-six, IL-one inhibition did not make it to regulatory approval, it lowers the risk of MI death and even reduces the rate of cancer. So, it's a proof of concept.
Methotrexate was not effective doesn't mean that the concept that chronic low grade inflammation drives this. And then we know that TNF inhibitors and actually good DMARR therapy lowers cardiovascular risks and can partially reverse insulin resistance and RA and that biomarkers including CRP correlate with much mortality in the general population. My final slide on this is the term that I love. I love the exposome. It's the measure of all exposures of an individual over a lifetime and how these exposures relate to health.
Of course, I think in terms of the immunologic exposome. You know, how we eat, how we sleep, how we exercise, how we de stress. All of this affects our inflammatory pathways and there is copious evidence from well designed trials that Mediterranean or paleo diets can lower inflammatory markers and promote health versus the standard American diet or the SAD diet with imprudent and bad fats at the other end. We know that moderate to vigorous physical exercise can drive down inflammatory markers may be partially mediated through weight loss and epidemiologically lowers the risk for respiratory infections. We know that poor sleep inhibits vaccine response and correlated with all cause mortality.
And finally, we know that chronic stress and social disruption is associated with a transcriptomic profile that has been called the conserved transcriptional response to adversity and shows up regulation of NF kappa B pathways. I posted a monograph called How to Train and Maintain Your Immune System that we give to every single patient in our clinical immunology center, which gives a no baloney, no hoax, no, you know, bug nutty, eat this berry and be healthy approach to health and tells people about eating real food, eating mostly plant based, exercising moderately, how to get there, how to use cognitive behavioral approach to sleep restoration, and most importantly, how to adopt a stepwise program to mindfulness meditation. So go to RheumNow, you can download this. We give it away for free. Print it up, use it all that you want to and be our guest.
The fact that IL-six is involved in these pathways in health and disease, as I'm pointing out, is so important for us. We know that IL-six augments pain. And why? Nerves can be activated by IL-six signaling via trans signaling and it actually lowers the threshold for activation. This has been shown in preclinical models and actually clinical models.
When you perturb people's sleep the beginning of the night, the AM circadian peak of IL-six increases, and people like Michael Irwin at UCLA has demonstrated it'll actually raise DAS scores over the near term future. And that in people with intercurrent mood disorders such as depression and chronic anxiety, multiple biomarkers are perturbed and we know that hypothalamic pituitary axis is disturbed, but the most reliable biomarker in major mood disorders is elevated IL-six both in CSF and peripheral blood. So, of these things I'm condensing and making sound bites out of a lot of science, but that's our topic to talk about this. Probably most interesting and most perplexing is the role of IL-six in energy metabolism and here I think you really get the flavor of this cis trans signaling. When we exercise, if you go out and you know burn a treadmill, get to your VO2 max, your IL-six level may go from two picograms to 70 or 100 picograms.
It can go up by, you know, nearly two log phases. Why does it do that? Well, it's very important in repair. The source of IL-six in that setting is muscle and it actually facilitates energy metabolism and glucose uptake acutely. Yet we all know that over time as we age, as we gain body mass index, CRP levels rise as do IL-six levels rise.
And over time there's an increase in insulin resistance and a trend toward adiposity with dysfunctional fat where macrophages can be polarized by IL-six. In the liver, chronic IL-six inhibits gluconeogenesis. So, is very contextual. There have been studies done with IL-six inhibitors that show that it actually can lead to partial reversal of insulin resistance. And what happens when you inhibit IL-six?
People gain weight. So, IL-six can drive central adiposity but leads to peripheral wasting just like a patient with chronic infection or cancer. And IL-six inhibition usually gains people will gain a few pounds over the ensuing six to twelve months. This was a very interesting abstract Mark Ginovace and a number of colleagues that actually demonstrated this and I was going to we'll show you this data. It's a ceruleumab study that showed that when they looked at the diabetic patients on ceruleumab with rheumatoid arthritis, regardless of the dose, that at the end of the day, fasting glucose fell, hemoglobin A1C fell almost by over a half a milligrams percent and weight gained slightly.
Trends in the non diabetics, but this is a proof of concept study that I think needs to be followed up on. This is a wonderful paper by Stefan Rohnsjohns group from Nature Reviews and Drug Discovery. And I was going to talk about it in terms of its this trans presentation. But what I will point out here as I close is that we started to think about this drug as a disease that would help rheumatoid arthritis. But, you know, over time we found that it's also very pivotal in other rheumatic diseases.
Giant cell arteritis was a pleasant surprise and it is now in my mind the standard of care where it will go in other large vessel vasculitides and PMR remains to be seen. JIA of both polyarticular and systemic variants is also very sensitive to this. And then this disease, Castleman's disease, this kind of bridging of inflammatory and neoplastic disorder, which is characterized by a good percentage of them actually being infected with a human herpes virus called HHV-eight, which encodes its own IL-six. And in these people they can have a chronic cytokine release syndrome and several IL-six inhibitors have been approved for this. In the last few years, in some countries, not all countries, IL-six inhibitor has been approved for NMO, neuromyelitis optica, a disease mediated by antibodies to the aquaporin-four ion channel.
And, you know, it comes back to the notion of why this is a B cell disease, antibody disease, this is a Rituximab disease. Well, in certain diseases, know, IL-six was initially called B cell stimulatory factor type two, and this may belie its mechanism of action. And then in 2017, with the approval of CAR T cell therapy for hematologic malignancies, which are now creating traction across the board in all types of different CAR T cells, About half of these patients develop an inflammatory syndrome that can be fatal. Emily White house, the first child to survive this, that was cured by CAR T cells, you know, would have died, but they saw a signal in cytokines that IL-six was profoundly elevated and she was rescued by this and it is now a rescue therapy for this disease. As we now go below the line, I think there's two areas of interest to us greatly.
One is in the area of treating immune related adverse events from cancer immunotherapy, particularly checkpoint therapy, where we have published a lot on this and a lot of our patients with chronic polyarthritis and chronic polymyalgia that can't get off steroids have been salvaged by this. And now there are several protocols, I don't know if I have this here, that are using IL-six in combination with checkpoint inhibitors out of the gate to see if it improves their activity and decreases their side effects. And then finally, the COVID-nineteen story that I'll come to in a minute. This is just to remind me to talk about the CAR T cell story. CAR T cells will only increase in scope and they'll increase in their lethality.
We now have what we call armored CAR T cells that do not long, don't get resistant to the tumors, And we need ways of controlling this. IL-six is very effective. It doesn't work for all patients. TNF may, anti TNF may still have a role, anti GM CSF may still have a role, and other therapies are still in therapy. This is just looking at cytokine release syndrome after these and showing the data.
You know, you don't have to be a statistician. When you see the levels, you get the levels of IL-six in these cytokine release patients, this is up five log phases. I'll point out that in patients with COVID, most of the IL-six levels are down here. Not very impressive compared to this. And then after a course of Tocilizumab, everything comes down.
Temperature, heart rate, blood pressure stabilizes, and all the biomarkers go in the right direction. So, this is our first hint that this is pretty hip stuff for cytokine release. And then finally, this is our thinking of IL-six as a preemptive target in cancer. Without having a lot of time to talk about this because I want to spend time answering questions and discussing this with Jack, know, IL-six functions through JAK STAT pathways and while several JAKs and STATs are solicited, JAK1 STAT3 seem to be more hegemonous in this activation pathway. And that there are downstream effector molecules from STAT3 that may contribute to tumorigenesis.
There are some forms of malignancy, particularly some forms of hepatoma and some forms of lung cancer where STAT3 is hyper activated and may actually drive tumorigenesis. And as I show on the bottom, this is clinicaltrials.gov study that is just getting underway where patients are given tocilizumab in combination with ipilimumab, an anti CTLA-four, and nivolumab, an anti PD-one, in patients with unresectable stage three or four melanoma. So, is how the study is being done, and it's going to be TOSI or placebo in combination with standard checkpoint therapy and the endpoints are how's the tumor do? How does the side effect profile go? Pretty amazing.
So finally, this is what Jack was asking me at the beginning. This is a brief paper. I'll do a shout out for Brian Mandel and the Cleveland Clinic Journal of Medicine. They have a curbside consult, COVID consult section where the articles are being posted by the day. Cassie has several papers up there.
I have a few. This is a figure that I put in the first edition of this. This is how we envision COVID-nineteen disease, the asymptomatic stage of viral recognition and acquisition, a triggering of PAMPs and generating inflammation and the virus establishes. We know that viral loads decrease over time. Even people dying have lower viral loads than they did initially.
Stage two, we're acquiring adaptive immunity, specific antibody and viral specific T cells and B cells. And here we start generating a more robust inflammatory response as the invaded cells die off, die off after the virus has penetrated them and they die of pyruptosis and release their products that damp receptors now pick up. And then in the unlucky small percentage develop this progressive end organ dysfunction and inflammatory syndrome that can look like a cytokine release syndrome. I do not like the language that it is HLH or it's MAS. It is not.
This is not CAR T cell cytokine release syndrome. You know, there are perturbations of cascades and networks of cytokines, but there's no reason to think that the same drugs, you know, will work equally as well in this pathway. There are different effector mechanisms that we're only starting to understand through big data, artificial intelligence, and hopefully the generation of biomarkers. Yet, when we measure cytokines here, yeah, IL-six, IL-one, TNF, IL-eight, IL-seven, all elevated. Cytokines such as GM CSF, are not normally detectable in healthy people are elevated.
Just like they're elevated in rheumatoid arthritis and synovial fluid. G CSF is elevated. You know, which are the bad actors? Interferon which is defective in stage one then becomes more abundant and maybe contributing to immunopathogenesis in stage three. So, there are now over 100 different strategies out there to parse this stage three, and we'd like to be able to treat people right here.
They've developed adaptive immunity, we won't suppress it, but they're not on a ventilator, they haven't developed ARDS, and they don't have irreversible disease. So, you know, I kept this slide just to keep it blank until like, you know, the other day, because you can find whatever you want to find in this space. There are studies being spit out of PubMed that are not even peer reviewed right now on this and take your choices. There are uncontrolled studies showing that all IL-six inhibitors have been beneficial. There are some that have shown less benefit than others.
And the question is, you know, why is this happening? Is it, you know, too advanced disease or they're using it in or is it the wrong drug? And as you everyone knows that there are now several large international RCTs that are being recruited that are almost fully recruited for both tocilizumab and ceruleumab, that we will have data in eight weeks and we won't be guessing. The next time that Jack and I talk about this, we'll have hard data on this. You know, I keep my fingers crossed.
I have equipoise that, you know, these are good targets to look at, but you know, there's other targets out there too. This is one of the this is ancient history. Wrote this way back in 04/13/2020. I think that the figure I showed you, you can go rip that off for your talks on this, but the data are different right So, these are the, you know, here's our buddies. I have a cut off Xavier.
He's standing over here. Maxine Dugados. They say that really bad is Or that tocilizumab is great, but they didn't release the data. And New York Times says that's really mad is not that they don't release the data either. Scientists.
You know, Lewis Thomas, one of my favorite all time authors and You know, National Book Award winner fifty years ago for the lives of a cell. He said, you know, in science, when science meets the public, the public is well motivated. They don't have guile, but they want to believe in things that could be hoaxes, you know. President says hydroxychloroquine sounds good to him and drinking Clorox and light sounds good. Yeah, why not?
Sounds, you know, Jason important guy, he said that. Investigators, Investigators, scientists, their makeup is that they're willing to say they're wrong when the data doesn't show it. So we have to stand up for science and hold the fort. So anybody that likes this chain of thought, please follow me on Twitter lcalabriesdl. I try to feed about what's happening in immunology, zen and fine wine and a little bit of what's going on in humanism.
So I think that's the end. Those are the diseases that we know about, but there's so much more coming down the pike. I think I'll stop and I'll kind of bug out of here.
Alright, Lynn, that was great. Thanks very much for that. I want to remind our audience that we're now going to do some q and a for the next fifteen-twenty minutes. Let's start with a few questions from the audience. So there was one comment about the Brazilian study on qtc intervals that said that the qtc intervals actually correlated with poor candidates, meaning that they were older and had more cardiovascular disease, rather than that not just the qtc, but that death in that study did not correlate with qt qt intervals prolongation, which was different, but it correlated more with poor candidates.
So again, that might be again, there's a lot of buzz around the cardiac effects, but really it seems like it's the comorbidities and the setup factors of age and obesity and cardiovascular disease and diabetes that everyone really should be worried
Well, mean, I think that there's all that, but I mean, so many of those studies are confounded by crazy drug drug interactions. And the vast majority of the studies that have shown the poorest outcomes and the most toxicity have been these hydroxychloroquine and azithromycin studies. And you know, like it's really not a hydroxychloroquine study. It's a study of hydroxychloroquine in a drug that has a serious drug drug interaction. So call it what it is.
I mean, am not worried about ten days of hydroxychloroquine monotherapy by and large in people who are not critically ill. I just don't know that it works but everybody on the other half of these studies is combining it with things like antiretroviral drugs and things like this. So it's not a study of one drug.
So, one of our, docs, Doctor. Horvath wants to know if you think there's any difference between tocilizumab and ceruleumab either I guess in what you treat or in these COVID studies, you think it makes any difference?
I can't imagine why it would be any different. I just can't. They're both highly effective drugs in the same space. They seem to work. I mean, they're both anti receptors, they both inhibit cis and trans signaling.
Their PDs are a little bit different, their PKs a little bit different. It'll be hard for me to imagine that one will be lights out and the other is going to be a negative trial. But it's not like, sorukumab that was an anti IL-six and had a different toxicity profile. But I don't know what do you think?
I kind of agree with that. I don't know that I'd have a different thought.
We'll have to wait and see. What's that? We'll have to wait and see.
Yeah, mean, think that that right now the real problem is you really can't be right or wrong right now because a lot of what's out there is bad data. One of our docs wants to know about tocilizumab and acute myocardial infarction. We talked about the search study and anakanikinumab study and where it worked and it didn't work. Would an IL-six inhibitor work in that setting? Cardiovascular patient, improving cardiac outcomes, could it work?
I don't even know what preclinical modeling is being done, but I will tell you that the Cleveland Clinic, we have a experimental protocol that if you have COVID and you have cardiac involvement by troponins, the study is using anti IL-one.
Checkpoint inhibitor induced arthritis, unresponsive to steroids and DMARDs, would you prefer to use a TNF inhibitor or an IL-six inhibitor?
Actually, at the moment, I mean, isn't like a lights out notion, but I feel that there are so many reasons to pursue anti IL-six therapy in there that Cassie and I have gravitated mostly to going to IL6 early. And there are both preclinical tumor models where anti IL-six actually enhances the anti tumoral effects of some of these therapies. So, we know that it has a decent toxicity profile there. We're experienced with it and it works very promptly. So no head to head obviously but just a comfort zone.
Wish Cassie would throw in on that shoes here.
What are your thoughts on targeting IL-seventeen in the cytokine storm?
Well, IL-seventeen, it has been examined and it is elevated. Absolutely. You know, if you look at preclinical modeling of cytokine release and you know, the oldest and simplest model is to take a mouse and expose it to LPS and then start measuring cytokines. And you know you see this you know TNF, IL-one, IL-six and then downstream, you know, this panoply of inflammatory cytokines. So when we talk about upstream cytokines, you know, IL-seventeen is downstream.
So I wouldn't expect IL-seventeen to, you know, have profound effects of turning off IL-six and IL-one and TNF unless you show me some data. Yet in maybe some end organ damage, it might be very, very, very vital. The other cytokine that nobody is enthusiastic about yet there are four clinical trials that we're talking about earlier is GM CSF which is not detectable in healthy people and is highly upregulated in the lungs of people with ARDS and other forms of advanced disease. It's the product of innate immune cells, these CD14 and CD16 activated monocytes and some people believe that it may be upstream of these other very basic inflammatory cytokines and we will know there's trials of anti GMCFS, IL-one, anti IL-six, anti interferon.
So a recent issue of Lancet, an article by Mark Feldman, Tiny Mani and others making a plea for TNF inhibitors in COVID. I mean, 3,000 words on the subject, they had a lot of good ideas. And there are a few trials of at least adalimumab and infliximab that I know of, but not as many as what we're seeing with other drugs, but do you think that that also makes some sense?
I think it absolutely makes sense. I think that, you know, look, we've been using TNF inhibitors in this IRAE world like crazy because they were available, were empirically used, you know, a lot of people are concerned about the response on, you know, the effects on host response to the virus. Yet, you know, there's no evidence whatsoever that anti TNF inhibits our clinical response to influenza. It certainly doesn't inhibit our vaccine response to influenza. All the models are, you know, knockout models, which I don't think are relevant here.
I would have equipoise to put a patient in a study of anti TNF. But as you say, I don't think there's any large scale anti TNF trials going on right now.
Do you think our patients, because we have so many patients taking drugs that target these molecules, might that be a reason why we're seeing so little COVID or so little bad COVID in our patients? A recent MMWR report of three zero eight COVID infected people in Georgia looked at the comorbidity relationships. A quarter of the patients had no comorbidity. And then the usual ones played out obesity, heart disease, etcetera. At the bottom of the list, one to two percent had a rheumatologic immunologic disease where the elderly, like 50, 60 year old having a five percent representation.
I think there's some evidence, I think it's partly because our patients are on these agents and their disease is well controlled. What do you think?
I mean, we've had some anecdotes of that of patients with very peculiar clinical courses to COVID-nineteen. At the minimum, I would say there is no smoking gun that they are overrepresented. You know, whether this all plays out, you know, let's look at the COVID RheumAlliance, you know, eight weeks from now dispassionately and see if we can get a little bit better handle on this. But so far, you know, I kind of like, you know, got my fingers crossed that your observation is accurate and we'll see.
Evan Leibowitz says that in his ICU and hospital, most of the COVID patients are overweight or obese. Is that a role for adipokines as a risk factor here or what do you think underlies the obesity risk factor issue?
I think that the common denominator of all these things, to me, is my hypothesis, is that it's a state of endothelial health. Every one of these comorbidities, whether it's type two diabetes or hypertension and obesity and chronic low grade inflammation, you know, contributes and cardiac disease, course, metabolic syndrome to accelerated morbidity and mortality. And whether that is because those cells are vulnerable to infection and there's already evidence that endothelial cells can be directly infected, whether it makes them vulnerable to complement mediated activation and a procoagulant effect. And as you know, that patients with COVID have hyperthrombotic disease, both gross clots and, you know, D dimers and clotting pathways. I think that is the smoking gun.
A beautiful paper ten days ago by Jeffrey Lawrence and group showing that endothelial cells can be activated and damaged by complement being activated by COVID via lectin pathway. Everything that you have sick endothelial cells, those are patients that get hammered. And that's what happens when you get old.
David Knapp asked a question about patients who are not severely affected or asymptomatic. It's supposedly eighty plus percent and there's a fifteen percent that seem to progress get respiratory symptoms and then subset of those who get really bad. But that's in that middle phase that you gave in that graph, but there are you put it you point out one line when in fact there are two divergent lines, with most people sort of having adaptive immune response that seems to work. And then there's others where it is insufficient or maybe there's an excess of an innate signal. What do you think is going on?
And how do we differentiate?
I do not think that people I don't think there's much evidence that people are dying of overwhelming viral infections. They are dying of collateral damage. And I do believe that this whatever you want to call it, I'd like to call it cytokine release syndrome because it's indigenous to this disease. It's not MAS, HLH, CAR T, JIA, it's its own dealio using the same players. And I think that adaptive immunity helps but somehow people are unable to turn off this process.
I keep using the term pyroptosis but that is what's happening here. That's when cells don't die, you know, neatly and quietly, they explode. And all of that, those damps and alarmins are setting off this pathway. If you look at the lung pathology, I've learned so much about this from talking to these lung pathologists and critical care guys, this is pretty unique. You know, only a small fraction of them get ARDS pathologically.
This is something different. I mean, you know, you got activated macrophages, got a lot of, you know, alveolar damage, but they don't all have hyaline membranes. This is something unique. The trick will be is that no one can magically draw that line. I was talking to some of the top pulmonologists in the world today about this on a conference call.
You know, when does the patient declare himself as headed for the ventilator? You know it six hours beforehand, but you don't know it two days or seventy two hours beforehand. You know, the oxygen goes up, these people have these resilient lungs, you know, are highly compliant. We don't have biomarkers for that, no.
So given that a lot of the damage is what accounts for the death and bad outcomes, should rheumatologists be playing a bigger role in managing COVID patients? I mean, all these drugs we're talking about are ones that we're good at.
Well, I think and I'm sure at your place is the same that any place that is doing clinical trials in COVID needs to have people like us, know, mano a mano, working on these protocols. And Cassie's on a number of them. I've consulted and Brian Mandel has consulted to virtually all the decision making. You know, they do need our help. You know, it's not that we're smart and they're dumb, in our sandbox with our drugs just like IRAE's.
So, I think this is an incredible interprofessional disease. You know, I said, you know, kind of fancy ourselves at the clinic as being at this nexus of room and ID. I said, you know, of all the gin joints in all the world, COVID-nineteen walked into ours. You know, this is this is what we do for a living here. So, we're very proud to contribute and we're very humble to learn from these guys.
You know, I've learned more critical care medicine now than I ever knew.
Herb Barath asked about the JAK inhibitors and their role in this syndrome and can they compete with the IL-six inhibitors, especially at that end stage there?
I do not you know I have been looking at this. I'd love to get your take on this and you know the modeling of this is very very different than the cytokine inhibition. You know, the first data was generated by, you know, machine learning that showed that, you know, baricitinib and ruxolitinib and one of these other ones I never even heard of, you know, would be particularly valuable in COVID-nineteen infection because, not because it was inhibiting cytokines, it's because it inhibited viral entry. You know, there are these crazy kinases that after ACE2 binding then contribute to membrane fusion. These are molecules I've never even heard of in my life.
And so, that's interesting, but that's upstream, I think, you know, that's in the viruses proliferating. I wouldn't want to be using a drug that inhibits interferon in the middle pathway, because you need interferon for the antiviral response. I know that there are RCTs of all of these drugs going on, but I would be wanting to use them in, you know, after adaptive immunity is established. Yeah, I'm probably wrong in all of this stuff, but you have to think of like where in the in the process is the MOA working?
Doctors Kisano and Fung have asked questions about measuring IL-six. Would you do them? What does it mean?
Yeah, great question. Thank You don't need it. You don't need it to manage this disease. To clinically recognize cytokine release is relatively simple. And CRP and ferritin and D dimers and, you know, falling lymphocyte counts, all of the things that we see in other cytokine release syndromes of other nosology are effective.
I told you the IL-six levels, which we do, you know, they go up, but they don't go up by more than a couple log phases and then you give tocilizumab or ceruleumab and then they go, hey, we checked the IL-six afterwards, it's going up. Well, yeah, it is going up. So what do you want me to do about it? Like, why did we measure this? I told you not to measure this.
If there was a cutoff, I would say do it, but we don't need it.
Last question from Doctor. Zuckerman. Is there a role for anti IL-six therapy to moderate the prothrombotic effects seen in COVID?
You know, it very well might be effective. I mean, you know that Ian MacInnis looked at endothelial health in RA patients on Tocilizumab, didn't find dramatic effects on flow mediated dilatation, but he found a lot of ex vivo effects on endothelial health. You know, we don't understand the hypercoagulability right now. It's not DIC, but it is a hypercoagulable state and a lot of people are hot to trot on this. You know, there are also now a handful of anti complement strategies in RCTs.
That may be a link between coagulation, tissue factor, endothelial health. My closing comment, Jack, is that first of all, this is so exciting to be able to talk expansively about this molecule, which there's so much to still be learned about. But I will tell you that six months from now, you know, hopefully when this thing is getting into the second half, hopefully into the fourth quarter, we will have learned so much. It never ever in our whole lifetimes would we have imagined this, you know. This took from 1981 to 1997 to learn this much about HIV that we've learned about in three months.
Right. And it's only gonna go exponential from here. I'm so grateful that, you know, I'll be here to throw my pebbles on the pile, as Sir Williams said.
Well, Len, thank you so much for your time. We really appreciate your leadership, your education and guidance on some very difficult issues. We look to you now and in the future to help us with this. So we really appreciate your being here. I wanna end with a pitch for next week and our speaker who is gonna be Joan Merrill.
She's going to talk about, what does COVID have to do with lupus. I think that's gonna be an interesting talk to say the least. And then also, we're gonna talk about, in the weeks to come, we're gonna have lectures not just from Doctor. Merrill, but you'll see we have a lecture the following week from, from down under, Philip Robinson, one of the fellows who started the Global Rheumatology Alliance, and Peter Nash. They're gonna talk about their experience, and then the week after that's gonna be John Kay updating us on biosimilars.
Glenn, thank you so much. Have a good night.
Everybody stay safe.
Thank you.
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