TNR Grand Rounds - -What Does COVID - 19 Have To Do With Lupus Save

Hello everyone, welcome to Tuesday night rheumatology. I'm Jack Cush with rheumNow. I'm here with Joan Merrill from the University of Oklahoma, the Oklahoma Research and Medical and Research Foundation, OMRF. Joan is a very well known nephrologist. I've known her since we both did fellowship.

We did that like two or three years ago. And she's gonna talk to us tonight about what does COVID-nineteen have to do with lupus? Hello Joan.

Hello Jack. Actually, you're wrong. That's not how we met. We met standing next to two posters and I kept bothering you and you kept telling me to go away.

Was that last year or was that twenty, was that thirty years ago?

It could have been forty.

All right, everyone. We're glad you're here. It's gonna be a very interesting session. I got a preview of the slides, so you're gonna like this. But wanna start off with a little bit of news that involve Joan and get some of her take on this.

Know, last week's New England Journal had a lead report about hydroxychloroquine, over thirteen hundred patients treated either with or not with hydroxychloroquine. These are severely affected COVID-nineteen patients. And it basically showed no difference in the outcomes, the outcomes being survival or intubation. Joan, does that surprise you that a lot of studies lately have really not shown any effect of hydroxychloroquine?

Well, the first study that really, came to the attention of the national press was this online YouTube video by that guy with very long stringy hair from France who, was announcing that it was a complete cure but not exactly telling us how thick the patients were to start with.

Isn't that a problem right now that we're getting all of our hints, not necessarily good evidence but hints from press releases, YouTube videos, you know, pre prints, it's a little worrisome.

Yeah. Well, at the other end of that spectrum there was a an article in the New England Journal, last week, cautioning us stupid doctors who aren't from Harvard, I guess, that we really shouldn't, like, draw conclusions when there isn't very much evidence, which I thought was a little talky downy because the fact is even the most august bodies of people who do this kind of thing and make recommendations have websites that change every day because what evidence we have, we've got to use, and it's an evolution.

Right. And it's really Corona A to Z and right now the Z lately seems to be, or the next Z seems to be the kids with the Kawasaki like disease. A lot of anecdotalism at this point and it's a worrisome manifestation, a worrisome outcome. Yeah. Second item, why are men more severely affected than women?

Is this proof that God is a woman?

No, you're just a weaker sex, God's probably still a man.

And I'm told that on a daily basis by my partners and staff. I don't if they're talking about me directly or my chromosomes, but there was a paper that, was recently published on a biobank study on heart failure that looked at over fourteen hundred men and it's almost 600 women. And they basically looked at circulating ACE2 levels and found them to be much higher in men than women. And they postulated that that maybe that's the reason why men are the ones who get the more severe manifestations of coronavirus.

That's interesting.

Yeah. Cause right now that is to me the big enigma. Why are the horror cases, I mean, the elderly are dying quickly with this. Is this, very few kids get it, but when they do get it, can get it bad. But the virus is not as non discriminatory.

You look in the ICUs, there's thirty, forty, fifty, sixty, 70 year old people, but the ones that plague me are the 50, 60 year old ones who have, who go to the ICU, get tubed, and don't usually have very good outcomes. And the question is why?

Why the six young men with strokes? What the heck is going on there?

Well, you're gonna tell us I think in your lecture, right?

I'll try.

Yeah, that's a good preview. I'm gonna end with two financially motivated reports. One is a report from the American Hospital Association say that hospitals in The US are gonna lose $50,000,000,000 a year beginning in March, extending to July 1. That's 200,000,000,000 in the first four months of this crisis. And then a recent report on Medscape today showed that hospital occupancy is down by at least 55% across the board.

And when they looked at, certain disciplines, there are a lot of people that are not going into the hospital, whether it's for breast cancer care or ophthalmology, rheumatology down sixty six percent, gastroenterology and hepatology fifty eight percent. The idea is that there's a severe financial consequence to all of this. And my worry is, is that the impetus to take us back maybe too soon? Do you have a feeling about return to normal?

Are you asking me?

Yeah. You're the only one here.

I never could define normal, so that's kinda hard question for me. But I would say this, I would rather get killed, have it done, and go back, and it's okay and it's safe.

Okay. I mean this is this is gonna very much matter, boil down to a matter of personal choice. Today Fauci, I watched the press conference. He basically said, if we go too soon, if we're too cavalier, there's gonna be a price to pay. And he basically was expressing caution.

And then the politicians came on and said, you're killing us, doctor Fauci, because the president is telling us get back to normal. And we don't know what to do, whether listen to you, the scientists, listen to our leaders, the president, you know, and obviously there's a finance and a reelection, business and economics. Then there's also truly

Well, Jack, there is a case to be made that it might be a little different from place to place, right?

Absolutely, absolutely. Yes. I mean, yeah, the story in Oklahoma City right now is going to be very different than it is in Bergen County, New Jersey. But who's to say that, you know, where those two stories are going to go in the next two months? That's going to be interesting.

And how is an individual supposed to know what their risk is? So that's the other thing that I think is keeping people home.

Well, and this is where your, you and I and all those that are on the line need to lead or find a leader that you can emulate because people are looking to us to give them the smart answers. Mean, I'm still amazed in week six or seven here, how many people I'm talking to that have been truly paralyzed by this situation. I mean, I talked to a patient say, who's got a severe neurologic manifestation and bad RA, and she's being put on rituximab. And the nurses at the infusion suite told her that, you know, her immune system is going be wiped out. And that that along with her RA and the COVID, she might as well, you know, write a death certificate.

I mean, she was an absolute panic. Obviously bad information, but I mean, this is again, this is where we have to lead, to really protect our patients.

Yeah, I think we really have to really think day by day. We have to really think about the inflammatory state of our patient. The other end of that spectrum is you take away all the people's drugs and they can't function either and they could even get worse. So, you know, we just have to be calm and practical and use what minimal tools we have while searching the literature for better tools because they're calming.

Right. I wanna remind our audience that, if you wanna ask a question, and please do, press the q and a button on the bottom of your screen and put in your questions. We'll be taking those and doing those until the top of the hour at the end. I'm going to bow out and hide myself, and Joan, you're gonna take over and drive this by sharing your screen.

Okay. This involves clicking a few buttons, so you'll have to bear with me for a second. Here we go. Here we are, Aman. Okay.

So I'm gonna talk about what lupus has to do with COVID nineteen. But spoiler, nothing. But there are some very interesting things that are happening in COVID nineteen, and lupus may be able to give us a lens to take a closer look at some of that. Now I'm gonna try to figure out how to click it. Oh, there we go.

Here are my disclosures, except I understand this is not a CME meeting, so we'll skip that. Okay. So I'm gonna start by presenting a lupus case, and it's probably a lupus case that most people here have seen somebody like, but maybe not very often. So this is actually way back when in 2005. I've been doing this case since then, and I'm even older than that.

But, it was such an illustrative case that I just keep showing it. This was a 17 year old, young woman. She'd had lupus for four years, so, obviously, she had real childhood onset lupus. Her past manifestations included arthritis, rashes, and really characterized by constitutional flares, fever, anorexia, weight loss. No history of nephritis, but she almost always had an anti double stranded DNA antibody at low c three.

So why did we keep our eyes on that? Because that's exactly the kind of patient you really expect to see some nephritis in. She'd been stable and just, you know, just to hedge our bet, we had her on MML since she was doing fine on two grams a day for more than six months. And then in March 2005, she showed to clinic with diffuse facial swelling, almost like angioedema, malar rash, lethargy, fevers, and anorexia, kind of like her usual flare. However, blood tests were sent, And back about a month before or less than a month before, she had a hemoglobin of 11.3, and now it was 10.2.

So that wasn't too scary. But the platelets had dropped from one fifty two to 53, And we noticed for the first time that she had a low albumin or she had last time. So after this clinic visit oh, the other thing I probably should mention is that her creatinine clearance was good, but she had elevated protein to creatinine ratio. So it looked like she was spilling the equivalent of more than a gram a day of protein. So we brought her back as quickly as we could, and by this time, the hemoglobin had dropped to 7.4, platelets were steady, c three was found to be low, and her protein to creatinine ratio was now in the nephrotic range.

So she was sent to the emergency room, but she didn't come to our hospital right away. She was lived pretty far away. So she went to a a hospital in Altus, Oklahoma or near there somewhere. And when she got there, her hemoglobin was 6.3, and her serum creatinine was up to 2.5. Immediately gave her a transfusion of red blood cells, and she received a gram of Solu Medrol each day for three days, which was the kind of industrial strength steroids that we were still using in 2005 in Oklahoma, but a bit gone out of fashion now because we don't think we need so much.

And that did help her platelets stabilize, but her hemoglobin kept dropping. She was retransfused and they actually put her in a helicopter and helicoptered her to Oklahoma City to see us. So at this point, her hemoglobin had she just been transfused, it was pretty good. And then over the next few weeks, it sort of hovered, you know, in safe but not so great areas, particularly given the fact that she ended up getting seven transfusions. Her platelets remained stable.

Her haptoglobin was very low. Her LDH was very high. A renal biopsy was performed which showed class four nephritis and diffuse microthrombi throughout the kidney. Her blood pressure went up on the March 22. She developed fever, so she was thought to have malignant hypertension.

And the following were given to her over this period of time, cyclophosphamide, heparin, plasma exchange for many, many exchanges, and high dose steroids. And then in the end, she was given rituximab and dramatically recovered. So what was this case all about? This was a patient with lupus who had hemolytic anemia, thrombocytopenia, microangiopathy proven by biopsy in small renal vessel, acute renal failure, malignant hypertension, and seizures. Boy, this sounds like thrombotic thrombocytopenia purpura, doesn't it?

Now, of course, TTP is not primarily a lupus thing. It the actual diagnosis is made because a person has a genetic variant of a protease that cleaves von Willebrand's factor, and that protease is called ADAMTS 13. So you inherit the propensity. Of course, you can be fine for a very long time, and then suddenly something triggers off a little bit of extra clotting in you and everything goes nuts. This protease isn't working well, the von Willebrand factor is accumulating in blood vessels.

The platelets stick to the von Willebrand factor sort of dimers and trimers and quadamers, and eventually you get microthrombi and it can be quite diffuse and quite life threatening. So that's an inherited condition. There's another inherited condition that's very similar called hemolytic uremic syndrome, primarily described in children but can be seen in anyone. And it's caused not by an inherited variant but by the Shiga toxin, which was originally identified as being made from E. Coli.

So these were people with E. Coli infections. Other bacteria also make Shiga toxin. There's something enough like it that it's called Shiga toxin. And what happens is that this toxin actually plants itself in the vasculature and triggers off a series of events so that you also end up with diffuse microthrombi, usually in the setting of something that had started to trigger off thrombosis.

So people are fine, and then suddenly this will happen to them. Now what is this lupus TTP thing? It turns out that there is a subset of patients who make antibodies to ADAMTS thirteen, and this happened to be an example of one of those people. And in one study, for example, it showed that if you look at the bottom here, people who have lupus and the antiphospholipid syndrome, about eighteen percent will actually have antibodies to ADAMTS thirteen. And what's interesting about that is they can't maybe they're not all bad antibodies or maybe they only get in trouble under certain conditions, which are poorly defined at this time.

But certainly eighteen percent of lupus patients with antiphospholipid syndrome do not develop this TTP like syndrome. It's quite rare. I'm guessing almost everyone has seen or heard of a case like this. Maybe they've seen or heard of four cases if they're old like me, but probably haven't seen it very much because it's rare. Here's another overlapping kind of syndrome, which gives you very similar clinical effects.

And this syndrome is called a catastrophic antifoxalipid syndrome. This was first described by Ron Asherton Asherson in 1992. He was describing a series of patients with rapid onset even over a week multi organ failure associated with small vessel thrombi. This is the theme we're gonna get here with small vessels that are clotted up, which is, of course, differentiated from primarily large vessel occlusions of the antiphospholipid syndrome. But remember that those tend to be sporadic, and this is a bunch of things happening at once.

So you can actually get large and small vessels thrombi rapidly happening throughout the body. Forty eight percent of those people do not have lupus. Forty percent do have lupus and the antiphospholipid syndrome, and I'm not sure what the other percentage are, I guess, undefined. This syndrome has an extremely poor prognosis. It's one of the worst kind of syndromes of this kind, but prognosis definitely improved once people started using some of the therapies that had been in place for TTP, such as plasma exchange, of course, heparin, and IVIG.

But usually these patients also will require steroids and cytotoxic, so it's a very aggressive kind of a treatment. A 100 of people with a catastrophic antiphospholipid syndrome have antiphospholipid antibodies because you can't make the diagnosis without it. Seventy percent have kidney involvement, and there's a high prevalence of involvement of the lungs, heart, brain, and skin. Homolysis is not all that common. It's been described in twenty six percent.

Note that you don't always have to have low platelets to have this syndrome. A good minority of these patients don't even have low platelets and a lot of them who do have low platelets, that's really not necessarily the primary pathology of the syndrome. We have a bunch of these syndromes that overlap, in this I couldn't fit everybody on the slide, I left out things like scleroderma renal crisis and the HELLP syndrome and other things that we actually see in the practice of rheumatic diseases. But here I'm lining up the catastrophic antidroxylic acid syndrome, and you notice I colored everything here yellow because I'm comparing it to some of the other overlapping syndromes. Hemolytic uremic syndrome is really quite similar, but there's some differences.

For example, you see shistocytes in hemolytic uremic syndrome, and it would be a little bit more rare to see antiphospholipic antibodies. Atypical hemolytic uremic syndrome is a version of hemolytic syndrome, and some say that this was discovered by the nephrologist, and some say they still have our lupus patients and put them into this category. It depends on who you are. But, it's a very interesting syndrome because it is actually now known to be caused by a disorder of complement. These people are inheriting variants in complement regulatory proteins or complement proteins.

And, basically, otherwise, is very, very similar to hemolytic uremic syndrome by the definitions and quite similar to the catastrophic antiphospholipid syndrome. And then, of course, next to there, I've got TTP or the autoimmune lupus version of TTP, which really are indistinguishable from each other clinically, except for whether you have a genetic problem or an antibody against the drug that had the genetic variant. Maybe they too are very much like the catastrophic antislostomy syndrome. Finally, I want to call your attention to disseminated intravascular coagulation, a much better known syndrome and a little bit more common. We see it a lot in elderly people with sepsis.

And there certainly are overlaps and there certainly are similarities, but there's some major differences with this one. This one often has bleeding and clotting at the same time. And you can see that in the lupus TTP, but you don't see it that often. This is often. So it's not a board question.

Lupus TTP is a board question. And I got that one right one year and wrong the other year. I don't know what happened to me. But anyway, this one quite quite frequently is bleeding at the same time as you see clotting. You also see hemolytic anemia.

So this is really a little bit more different than the catastrophic antiphospholipid syndrome clinically. But we're gonna move on and talk about that a little bit more. So BIC actually has a different pathology or although they overlap to some extent, what happens in DIC is that there's sepsis or trauma or some trigger like that, which causes endothelial cell damage, and this activates tissue factor in the endothelium. And then you get thrombin production. And for various reasons, the thrombin production is extreme, and there's a consumption of all the fibrinolytic and anticoagulant factors, which is much more strong than any consumption of clotting factors.

So it's called a consumption coagulopathy and they accumulate fibrin in small and mid sized vessels and then they get organ failure. And then they also get depletion or consumption of platelets and that causes bleeding. Now the other thrombotic microangiopathy syndromes that I showed you on that slide all share something quite interesting, which is they all have an integral part of their pathology mediated by complement. All of them. So they may be triggered by infection as well or trauma, or we don't know quite what, but there's autoimmunity going on.

We do know a lot of the inheritable and nonheritable predispositions. So we we've talked about the inherited variants of complement. Guess what? Not only have those been found in the atypical hemolytic uremic syndrome, they've been found in the catastrophic antiphospholipid syndrome as well. So we don't always know which one we're talking about in an individual patient.

We talked about the inherited variants of ADAMTS 13, and we talked about the Shiga toxin. So all of these different kinds of ways of getting to this this final common pathway actually does lead to a a very similar overlapping pathway. The important thing to know is this is not a consumption coagulopathy, and you don't have a lowering of protein c and protein s and anticoagulant factors the way you do with EIC. So it's somehow a very strange interplay between complement inflammation and coagulation. It may not be surprising then that the treatments for these conditions are a bit different.

So for disseminated intravascular coagulation, pretty much all you have to do is anticoagulate and treat the underlying cause. If it's sepsis and you know the bacteria, you hit hard with antibiotics, Do a little praying, but you really don't go into treating it like an autoimmune condition. All of the cognitive associated thrombotic microangiopathies require more than that. Yes. You do anticoagulate.

Yes. You would give something for the underlying cause if you know what it is, but you need high dose steroids. You need plasma exchange and or IVIG, and you might consider rituximab or some other immune suppressant as well. Well, wait a minute. If these are complement associated TMAs, what about targeted complement inhibition?

Here's my little picture of the complement cascade, and I'll remind you that there's sort of three major pathways. The classical pathway that we know from lupus involves immune complexes triggering off a series of cascade of complement proteins. The lectin pathway associated with microbial carbohydrates triggers off a different series of events. And the alternative pathway, which starts on activating surfaces, could be in the context of infection or not, triggers off its own specific kind of events, all of which in all cases leads to something called a c five convertase. C five is this clinical linchpin of the whole place, and so it gets cleaved into either c five or it gets cleaved into both c five a and c five b.

C five a is a fascinating little character because it triggers inflammation like crazy. It's a very nasty little molecule. It activates monocytes and neutrophils, which are, by the way, key players in the innate immune response. It actually can trigger them to go around in circles and suddenly you get a lot type one interferons going on, and it also activates coagulation. So it's a nasty little player and doesn't that sound like lupus and doesn't that sound like microangiopathy?

C five b meanwhile, of course, becomes part of the membrane attack complex meant to destroy the pathogen, but also destroy some of our own cells while it's at it. So we found out that the various thrombotic microangiopathies that are complement mediated can trigger any one of these pathways and sometimes two. The alternative pathway is the one that is most frequently activated by atypical hemolytic uremic syndrome, but some of the others can do the same thing and then they can activate the lectin pathway or the classical pathways. So complement activates platelets, complement induces tissue factor on endothelial cells, monocytes and neutrophils, and this is all very intimately related with what goes on in an innate immune response. What's an innate immune response?

Remember, that's what we do when we don't have any antibody memory of some pathogen coming in our body. You get a new pathogen, you haven't stored up some antibodies that's gonna recognize it because you never saw it before. So you're gonna get a lot of innate immunity going on. I'm getting towards COVID. I know you've guessed, but that's what's happening with this new virus.

We've never seen it before. So we're gonna be relying heavily on our innate immune response. And when we get to the point where we're gonna have an adaptive immune response and start to make antibodies, We're not sure exactly what the right antibodies are. It's gonna take us some time. We're gonna make a lot of different kinds of antibodies to try to see if we can get rid of that pathogen, and some of them are gonna form immune complexes.

So we may be, you know, we may be potentially activating any of these pathways. So a complement I'm sorry. A complement inhibitor, eculizumab, has been associated in TMAs when treated people with TMAs have been treated with decreased interferon signals and decreased evidence of all of these pathways. Quite interesting, but also the the interesting piece of this is that the interferon signal goes down, suggesting again, that the complement system, the interferon system, all of these inflammatory pathways and the coagulation pathway are very much tied with each other with back and forth crosstalk and sort of perpetuating each other. Let's look at eculizumab a little better.

What is it? It actually binds to c five and it inhibits the c five convertases from cleaving it. So you don't get that nasty c five a, and you don't get the membrane attack complex. And it pretty much shuts off a whole lot of the self perpetuating aspects of these diseases, at least in theory. Do we have any double blind placebo controlled trials to prove that it works in these conditions?

Well, these are rare conditions, and no, we don't. But there are a number of published case series which show surprisingly dramatic results in the catastrophic antiphospholipid syndrome, in atypical hemolytic uremic syndrome, in typical hemolytic uremic syndrome, in autoimmune TTP like syndrome or lupus TTP like syndrome, in transplant associated thrombomicroangiopathy, one of the ones I couldn't fit on my slide before, in the HELLP syndrome, another one I couldn't fit on my slide before, but our lupus patients get that at the end of pregnancy, very serious condition. And also now there is a anecdotal observation about COVID nineteen getting better. What am I talking about? Well, it turns out that in the past months or two, there have been increasing reports that really weren't that clear from the original reports from China and the original ones from Europe.

But it started in Italy and then started spreading around the globe. Lots of reports from New York now that there's a striking prevalence of thromboembolic events in this disease. Quite unexpected if you think about other viral infections and you do get some thrombosis, but this is quite unexpected related to them. And that includes some of those serious coronavirus infections, SARS infections. Of course, our population of affected people are older and they have comorbidities.

So at first, you know, maybe it was attributed to that. But in one series of a thousand twenty six patients who had COVID nineteen infection, forty percent were found to have thrombotic risk profiles like blood tests. And in a study of a 184 ICU patients, there was thirty one percent in incidence of thromboembolism, serious thromboembolism, despite the fact that these patients were on thromboprophylaxis at regular doses. Also increasing reports of severe thrombotic events in younger people without known risk factors, And then these odd reports of patients developing severe gas exchange deficits, even though by imaging and by listening to their lungs, their lungs seem to be very well aerated. Now this was widely interpreted as disseminated intravascular coagulation.

Yeah. They saw some low platelets, although they weren't all that low. There was widespread thrombosis, and there was significantly elevated LDH and D dimer, and all of those things do suggest DIC. And so that's what was being reported in the tabloids. And you can see there's been a lot of reporting in the tabloids.

My favorite is doctors don't know why. So one way of trying to make sure we understand what's going on in these patients is to look at autopsies. There are not a lot of autopsies. Most of them are not systematic. They're not looking at every patient coming down the pike.

But a lot of them are trying to find people who don't have too many other comorbid diseases, but some of them even so do not find a thrombo thrombotic microangiopathy. But here's a report from Macro looking at the skin and lung from five patients who had respiratory failure. He did not find a lot of inflammation in the lungs. He found fibrin deposits in septal capillaries. He had some neutrophils, kind of an innate immune response infiltrating the intra alveolar septae.

There were microvascular deposits of complement components and nanospinding lectin associated serine protease, which is associated with the complement cascade. So three out of the five patients had purpureic skin lesions, such as had been described in the catastrophic antiflexible lipid syndrome. And again, they found a thrombotic vasculopathy and and deposition of complement. And they found that in both affected and normal skin. Two of the five cases, they actually found the COVID-nineteen spike glycoproteins sitting there in the same spot with complement components, both in the microvasculature and in the lungs.

So they concluded that this was a catastrophic systemic microvascular injury mediated by activation of the alternative and lectin based complement pathways. If you think about it, here we've got the picture of the COVID-nineteen thrombo micro angiopathy affecting these same pathways we were talking about before. And there's just one more little interesting factoid that I'm not sure we ought to make too much of yet. It was in a prepublication, but it described a nucleocapsid protein of several of the SARS viruses, including SARS CoV two, which is our virus, binding directly to key protease and the lectin complement pathway. So it is possible with things triggering off complement all by itself.

So now I've lined it up with the other p t TMA syndromes. And what you can see, I what what I've colored orange all the things where caps doesn't look like DIC or some of the others. But as you can see, it's matching caps almost completely. Now is it the catastrophic anti phospholipid syndrome? No.

Obviously not. It's a viral associated thing, and we know what's causing it. Or at least by circumstantial evidence, we're pretty sure that wasn't a coincidence. But they there are now reports of leukocyte, coagulant, or antifrostolipid antibodies found quite frequently in these patients. I would caution you, we're not sure what that means because once you get people who are extremely ill and or septic, these antibodies tend to show up, and we're not sure whether they're pathogenic or not.

And there's a lot we don't know about these reports, but they're there. So I colored it yellow, but if you want, you can cross out that yellow one, and it's still very much like the catastrophic antifrostolipid syndrome. So in summary, we have a potential disease model here. The virus gets it, you breathe it in, it gets into your upper respiratory tract, it goes down into your alveoli. It's gonna it's gonna like to be there because it has receptors on the the the on the cells in the lung there.

And so there it is. And then there's an interface right there with the small blood vessels that nourish the and where the oxygen goes across in your lungs. Now there's gonna be a obviously, an innate immune response. You're gonna get neutrophils. You're gonna get monocytes.

You're gonna get type one interferon. You're gonna get tissue factor, and you're gonna get little clots. And that's pretty much what seems to be going on in a reasonable subset of these patients. So in conclusion, COVID nineteen is associated with a life threatening complement mediated inflammatory thrombotic microangiopathy, which unlike the other conditions that are so similar to it, does not appear to be rare. Most of the patients who develop this disorder are not receiving the interventions that are thought to be necessary to treat this.

The recommendations for disseminated intravascular coagulation, which a lot of major medical bodies are still calling this, are anticoagulation, and in this case, it would be an antiviral treatment. And, you know, we've had some success with anticoagulation. We've had some success with antiviral treatment, and people are dying anyway. Recommendations for complement mediated thrombotic microangiopathies also include other immune suppression. Well, there's been kind of a patchwork attempt at immune suppression in some of these patients around the world, but nothing very organized.

There are some clinical trials going on right now. We don't know the results of particularly. Although one IL six targeted agent seems to have not done very well in the clinical trial. But also it's recommended to do plasma exchange and or give intravenous immunoglobulin in these kinds of cases. And more recently, there's a growing case, at least anecdotally, for trying complement inhibition in these patients.

And now I have to turn the thing back, right? Did I do it? No?

Yes, you did. Yes, you did.

Oh, good. Okay.

Can you Alright. That was very good. Let me see. There we are. I'm back on screen with you.

That was excellent. Thank you very much.

Thank you.

Yeah, I think the question is, do you see this, the treatment of this, if we are gonna call this a complementopathy or a thrombotic microangiopathy, Do you see the treatment of this being different than how you would treat catastrophic antiphospholipid?

You know, obviously we always have to pick from all of our options for any individual patient that we have. And a lot of what, when I make that long list of treatments that you give, what really happens, we get a lot of patients I shouldn't say a lot because it's not that common, but we get patients with lupus who have partial syndromes. So you can start with high dose steroids. You can give a few plasma exchanges. They're all better.

You can stop now and then maybe give them something to to keep them, you know, to keep them suppressed, but you don't have to keep hitting them with new things. So I think I think you do have to tailor therapy to what's going on in the patient day by day. But there is an interesting case to be made for plasma exchange in sepsis or what they call viral sepsis, where you get the cytokine storm because it's actually taking those cytokines out. And of course, one of the things that is currently being kind of hoped for is that, convalescent plasma will help these people because people have now made some decent antibodies at work. So wouldn't it be cool if you thought about the idea of doing plasma exchange, but instead of putting in just like some plasma, you give them convalescent plasma as the replacement plasma.

That could be kind of a cool idea.

Yeah. Anthony Fauci talked a little bit about that this morning as a future new therapies. When you mentioned convalescent plasma, you also mentioned, well, you might as well, for that reason, might as well even try gamma globulin or IVIG these patients

Which as might work for the sepsis aspects as well. That's the point I'm making is that these kinds of special treatments for these conditions that have to do with all kinds of factors you're trying to get rid of that are causing coagulation will also get rid of a lot of the factors that are causing cytokine storm.

So I thought when you started your lecture and said, what does COVID-nineteen have to do with lupus? And you said nothing. I thought, oh, shortest grand rounds ever. We're done. But I'm glad that you gave us the rest

of You told me to make it short.

So do you routinely test for ADAMTS in patients who you suspect is having either thrombotic microangiopathy or the catastrophic antiphospholipid syndrome?

I don't because I never see them. I just see lupus patients as most people know. But if it's a lupus patient and they get hospitalized with one of these conditions, which is quite rare again, you know, maybe every couple of years we have somebody like that. The I I don't have to order anything, Jack, because the rheumatology fellows will order it.

Yeah. They seem to find a nice long list and

Yes, they'll order all kinds of things I don't need because I know how to treat it. I'm not sure I care. If they've got lupus and they've got this, I figure it's a bad thing and I know how to treat it.

So again, sticking on treatment then, do you think the role of immunosuppression more aggressive immunosuppression should be part of the regimen here? I agree with you, right off the bat it's gonna be steroids and the next few moves might be enough, but should there be a role for stepping up the immunosuppression in such patients?

I think there is, but I think, a lot of what's going on today is a little bit like rheumatology fellows. I shouldn't bad math rheumatology fellows. We may have some brilliant rheumatology fellows listening to this tonight, but

We do. We do.

Everybody is, jumping to anti IL six targeted therapies because IL six is important in cytokine storm. I keep going, how do you know that's enough? You know, these people are sick. Let's whoop them and then worry about what targeted therapy would work.

All right, so Doctor. Fung Don in Waco says COVID-nineteen patients show an increase in von factor, but not so much in ADAMTS. The clinical picture is much likely to be described as in caps and antiphospholipid. Is this part of what you described?

I think so. Well, if you get increased von factor and you're in a situation of clotting, you're going to trap platelets and you're gonna increase your risk for clotting. There are lots of ways to increase von Willebrand factor, not just having a inherited deficit of what pleases it. Know, there are other ways to get too much.

Do you think there's a role for rituximab in managing any of this?

Well, the reason it got tried in the catastrophic antiphospholipid syndrome is because it was new and we were all behaving very much the way I'm accusing people of behaving today. We didn't know what to give so we gave something strong and new and it anecdotally seemed to work very well. It seemed to turn things off in some of these patients where you couldn't stop it.

Yeah, Do you think our patients with lupus might be protected from catastrophic anti phospholipid or these thrombotic complications because they're on chronic Plaquenil and the antithrombotic? Well,

I know factoids about that, but I don't know the truth. But I'll tell you my factoids. My factoids are that we once did a study and we're not the only people because somebody else actually published their study. We just showed ours at some ACR meeting. But if you look at a population of lupus patients and you just split in half those on Plaquenil and those not on Plaquenil, at least retrospectively, you get a lot more thrombosis in those not on Plaquenil.

Okay. So it seems possible, but you're right. It's not necessarily a factoid.

It's a factoid. Yeah, it's not the truth, it's a factoid.

But if I misspelled factoid, it could become a fact.

That's, yeah, but since I am known to perseverate, I'll keep going till I get to factoid.

So, Doctor. Leibowitz, Evan Leibowitz says, great talk. How about attacking something more proximal in the complement pathway like C1, esterase inhibitors?

Sure.

Yeah. All right. Do you have any experience or knowledge of eculizumab either in caps or in these COVID patients? I can tell you eculizumab is in clinical trials in COVID-nineteen patients.

Yes, I saw it on clinicaltrials.gov. Yeah, I know that.

So do you have any experience with using eculizumab in lupus patients?

We have a little bit of anecdotal, you know, experience, but not in this situation. I've actually never had it in this situation, no. Not in a like a lupus TTP or anything like that, no. But there are certainly, there's case series in CAHPS.

Umesh actually asked a question about, do you think that the concept you described with COVID, do you think that is lectin mediated or immune complex mediated activation of complement? As you said, lectin has been known to activate the SARS has been known to activate the lectin pathway.

Yeah. Well, you know, the slide I showed just showed you what's been published and what, you know, somebody observed or was able to kind of, you know, implicate. That doesn't mean that all three aren't involved. So, you know, how I'm looking at it is we're not sure, and it may not matter at this point, but we're not sure whether this whole thing isn't just happening from the innate immune response, in which case you don't really, you're not going to invoke immune complexes triggering off complement. But, you know, these people are trying to make antibodies.

They'll start early and they'll try and they may fail. And that's exactly who's gonna, in my opinion, it's exactly who's gonna make immune complexes because they've just got all these antibodies that aren't working and they're not getting rid of the virus, and they're not getting opsonized, they're floating around and maybe even attaching the parts of self as, you know, what happens in autoimmunity. If that happens, then it makes sense that it could be the classical pathway.

So, you've made a case for this syndrome in COVID looking like CAPS, and that's part of a family that you described though with these complementopathies. Where do you see that going in rheumatology and lupus care? I mean, do we have to wait for the disaster, for the fire to occur before we get

Well, as rheumatologists, we have a very important choice to make. Are we gonna call this atypical hemolytic uremic syndrome? Then we can just send it to nephrologist, you know? Or we could take care of these patients because we are the real immunologists. Then we have to decide who we are, don't we?

Yes, I agree. I agree. I think we have to be thinking about this because this is a very small, and this is one of the areas where a rheumatologist could get involved in the management of the COVID patient.

I frankly am, I'm kind of on a crusade here. I think this is a place where rheumatologists should get involved in the management of COVID patients because people are still dying until they figure out a way to cure them without us, maybe we should help.

Right. Are you familiar with the COVID toes thing? It's not something you can buy on Amazon. It's No. Sort of dusky looking fingers that sometimes look like chill blames or first

sign is Seeing in lupus and seen in caps.

Mean, this is where you drop the microphone I and walk off think that you're done. I'm not sure what this means, but I'll ask this from Doctor. Fung, antibody directed enhancement might occur in patients after pokes infectious adaptive immunity has developed. IVIG was suggested. What's your comment?

IVIG is one of the treatments, yes.

Okay. Do you use a lot of IVIG or is it

We do because think about it. If you if you've got a person, particularly if it's a somewhat older person with comorbidities, you know, lot of it I didn't mention, but a lot of these autopsy reports were showing bacterial pneumonia. These people are getting super imposing pneumonias, right? Because they're sick. So you'd rather give IVIG than something that's going to knock out what little immune system that's still functioning for them.

Yeah.

Doctor. Quinnette down at Oxnard in Louisiana asks, what's your strategy for getting insurance or hospital approval to spend hundreds of thousands of dollars on drugs like eculizumab? And a lot of the treatments we're talking about here are really expensive. This a treat first, ask questions later and hope that it doesn't become an issue or

Well, I mean, if somebody's dying in your unit and you can't get approval for eculizumab, I think we start with high dose steroids and see if you can get somebody in there to do plasma exchange. You know, you start with things you can do. And we didn't used to have eculizumab. We used to take care of these patients. That that case in 2005, we didn't have then, or we didn't know we had it.

I don't know when it came out, but we didn't know we had it.

David Collier says his daughter seeing patients with COVID toes, propuric and, you know, toes like lesions like you described, but all of them were negative for COVID. So when you see that in your clinic, what else are you thinking? Immune complexes or is this really a

I I I would check a d dimer. I mean, there's two things you can do. I would check a d dimer. It's gonna be sky high if it's this. I check, DH could be high.

I would, you know, I would check for c reactive protein is often high in these patients. This, you know, there's a list of things you can do to kinda see if you can make a case that there's inflammation and coagulation going on. And then, you know, if if if you're lucky and somebody has a you know, somebody's a little bit younger and isn't diabetic and has kidney failure, somebody may do a biopsy for you and then you can see what's going on in there.

Doctor. Nimri asked a question about what's your cutoff before you start to get aggressive in what you may think is a compliment mediated disease? Is it a certain platelet count or a certain level of hemolytic anemia or if you're thinking it, you're doing

Well, if you have, you know, I was sort of saying this is a spectrum. In COVID, we don't see hemolytic anemia or we don't, I mean, we don't seem to be seeing it. I'm not even looking at that point, if it is, it's not bad like lupus because we're not getting that, you know, really crashing kind of, hemoglobin. If you saw a lupus patient with crashing hemoglobin like that, that's hemolytic anemia. Now hemolytic anemia all by itself will respond to steroids almost always, and you really don't need to do too much.

But then when you start to see the platelets going down at the same time, and you start to see, you know, kidney function deteriorating, or, you know, protein, a lot of proteinuria coming out, you're in trouble, and then you act very, fast. I think in COVID, it's sort of the same way. If you see a person with hypoxia and this is sort of a classic picture, they've got hypoxia, but their lungs aren't all that bad. Maybe they have a little little ground glass opacities on their CT scan, but not a lot. They seem like they ought to be well aerating, and they're not.

That tells you that the microvasculature of the lung is clotting up. And then you look for all those other signs, and then I would at least be aggressive in some way. You know, if you if if you're in this situation where people go, how dare you? Then try IVIG because no one's gonna say how dare you for that.

Do you think that all COVID positive patients should be put on aspirin as peri rush or that all patients with COVID who are hospitalized should be put on anticoagulation?

I think there's a lot of talk going on out there right now among hematologists and cardiologists. And there's a whole, sort of group that are now calling for not just prophylactic anticoagulation, but full dose anticoagulation as soon as they're hospitalized. Then there's another group that says no, when they get really sick, we'll do that. But almost everybody wants to do that.

One of the docs asked a question about the role of IL-one inhibitors in severe inflammatory responses in COVID. One of the news items I was going to mention was a report from Lancet Rheumatology last week. Anakinra was studied in COVID positive ARDS patients, not ICU admitted. They had to have a high CRP and a high ferritin to get in. Twenty nine patients were treated with anakinra, seventeen They're not really it's not really it's a pseudo controlled study.

It's not really nonetheless, day 21 outcomes were better in anakinra, ninety percent versus controls fifty six percent. And there were actually more like discharges on anakinra. Obviously, anakinra lowered CRP and respiratory function better than did the controls that didn't get anakinra. What's your take on that?

I have two things to say about that. The first thing I have to say about that is that it's theoretically very promising because IL-one is very important in cytokine storm and all of these different connected interplay of cytokines. It's probably a good place to think. And the second thing I'm gonna say about it is I knew they'd finally find something to do with Anakinra.

Yeah, I know. It's a drug that I actually did a lot of trials on early on in the night, hence I still am fond of it.

Most who've actually utilized it think it's a good truck, but it never really found a place did it?

So Evan Leibowitz has talked about his experience in his center where by by being involved in chart reviews and whatnot, he asked to be part of the task force, and he found it to be really interesting and useful to be in these intense discussions with ID, pulmonary critical care, and hematologists. He said he's learned much. I'm sure he's actually taught them a lot, especially about the appropriate use of our drugs. So I think we should be advocating for rheumatologists taking a bigger role there.

Yeah. Well, think we should be because I remember when I was a fellow, I was also a rheumatology fellow once, believe it or not. And, I remember that you'd be in the middle of the night, you'd show up in the ICU and you'd see the hematologist, the infectious disease guy, the rheumatologist. That's who they called, and then you knew they didn't know what was going on.

And they were so glad that you showed up because maybe you can write something in the chart that's gonna actually look good because right now we don't know what we're doing. Has there been a COVID thrombosis in a patient with lupus on either rituximab or Benlysta? I don't think we know the answer to that. I think that the next week's authors or speakers include Philip Robinson, the guy who's leading the Global Rheumatology Alliance, and he's going to maybe give you a new data cut on the patients they have admitted. And there are plenty of lupus patients, plenty who've been on rituximab.

I don't know about Benlysta, but we'll hear about that maybe next Do you have any experience with COVID, lupus and those two drugs?

Well, in Oklahoma, we don't have enough COVID patients to be able to say too much about lupus, right? Because that's even a subset of a subset of a subset. But I have talked to colleagues in New York because I was curious. And the problem is that everything is so disorganized that they can tell me, think the patient was supposed to have been on, but they have no idea when they got their last dose. But there certainly are lupus patients in the intensive care unit and quite sick.

Right. Yeah. I mean, our drugs do not protect our patients. There have been plenty of reports, we've covered that on RheumNow. Doctor.

Saab asked a question about are c three and c four low in COVID patients? My experience is that they have not been low in COVID.

My my I I don't know who's testing it because I haven't seen anything published on it, and I and, you know, nobody around where I am tested.

Okay. Do you wanna ask a question on the audience?

But, you know, Lucas Lucas is very special because it's got a, you know, it's a complement consumptive kind of a thing. But you can have complement activation without having a low C3 and C4. So, you know, you yeah.

Especially in the face of overwhelming inflammation where complement is gonna behave as an acute phase reaction as well. It's like your white count, you know, because of infection of four, it could be really worrisome in a lupus patient. Yeah,

yeah, yeah.

So all right, I think we're gonna close it right there. I want to thank our audience for these questions. I do want to remind the audience that next week we're going to have speakers from Down Under, And that would include Doctor. Philip Robinson. I have that slide here.

Let me see if I can make this a little bit bigger for everyone. Sorry about that. And this is gonna be next Tuesday's grand rounds. Philip Robinson, who has led the RheumCOVID registry by the Global Rheumatology Alliance, and Philip's from Queensland has been a reporter for RheumNow. And Peter Nash, a good friend from Australia is gonna also be on hand to talk about COVID from Oz.

I guess Oz means Australia. So should be a really interesting session. These guys are real chatty. They got a lot to share. I think it's gonna be really quite cool.

Joan, thank you so much for doing this. You were just wonderful as expected.

Thank you for having me.

All right. Good night, everyone.

Good night.