RheumNow Podcast - Novel COVID Rheum Trials (5.1.20) Save

It's the 05/01/2020. This is the RheumNow podcast. I'm Doctor. Jack Cush, executive editor of roomnow.com. This week it's clinical trials regarding COVID-nineteen.

I reviewed them all this week and there's been a lot of press releases really from like the twentieth to just yesterday, including the New England Journal, a lot of reports of concern to the rheumatologist because it concerns your drugs. And I'm going to review these in basically sort of a mini grand rounds weekly podcast. So if you're watching, you can actually see the screen and I'm going to show you my slides. I think you'll find this, informative. If not, you can listen along at home and that'll work as well.

So let's start out by talking about, there we go, let's start at this, this week in clinical trials. I think the issue here is that our patients are supposedly immunosuppressed. Our patients are presumably taking immunosuppressants. But yet we are telling them, do not stop your prednisone, do not stop your DMAR, do not stop your biologic in this COVID era. If you get infected, then give me a call and we can discuss.

The interesting thing is that we've noticed very few of our patients being infected, very few of them in the ICU, and even fewer of them, dying from this coronavirus infection. So the question here is, do our diseases make our patients at risk? Does disease activity increase risk? Or is it the drugs that we use that can change risk, either help the patient or protect the patient? And there's actually some new information this past week that we should review.

First, an update on the, roomcovid.org registry, the COVID rheumatology registries, one going on worldwide, one done by ULA combined. We're over a thousand patients, it looks like. You can go to the websites and this is the data you'll get. These are patients with our diagnoses, most of whom have rheumatoid arthritis, next psoriatic arthritis or spondylitis, and next is lupus at about twelve or eight percent. But these are patients who are infected with the coronavirus who've been enrolled in this registry.

Around sixty five percent, two thirds of patients are female. In the worldwide registry, nearly thirty percent are elderly. In the UR registry, it's almost fifty percent. And it looks like two thirds to eighty percent of patients are on DMARDs at the time they're enrolled, and, twenty two percent are on hydroxychloroquine. When you look at, biologic DMARDs, it's about thirty to thirty four percent of patients enrolled are on a biologic.

JAK's less common, steroids about a third of patients. So far we don't have any readout on this registry, but from the two registries and what's reported, about two thirds of the EULAR COVID patients have been hospitalized. And in the COVID room registry, there's been a nine point two percent of patients who have actually died from this infection. Again, this data needs to be verified. Yesterday, the New England Journal, Haberman et al, including Jose Scher, thank you Jose for sending this preprint to me, reported its experience at the NYU Langone Medical Center accumulating patients in the month of basically March, and they accrued eighty six patients with IMiDs, immune mediated inflammatory diseases.

That includes RAPSA, psoriasis, AS, and IBD patients who were infected with the coronavirus or who were suspected as being infected. From this cohort, it looked like sixteen percent of their patients were admitted to the hospital. Those who were admitted were more likely to be older, have hypertension, diabetes, and COPD when you compare them to the ambulatory patients. This rate of sixteen percent is actually below, but yet on par with the New York City, Health and Hospital Corporation rate of about twenty nine percent. So in New York City, the epicenter of coronavirus infections where there's a lot of deaths like, you know, I don't think we have eighty deaths in Dallas.

In New York, they're having three hundred to five hundred deaths a day. But anyway, the hospitalization rate in New York City is twenty nine percent currently. So this is low, meaning our patients aren't being hospitalized, at the same rate. Certainly it's not more if they were immunosuppressed, they think it might be more. But when you looked at the therapies that were reported in this New England Journal article, you can see patients who are on steroids, hydroxychloroquine and methotrexate were more likely to be hospitalized.

So for instance, methotrexate amongst the hospitalized patients forty three percent were on methotrexate. Amongst those that were ambulatory over their corona infection only fifteen percent were on methotrexate. So does that mean those patients are more likely to be hospitalized? Well, let's look at what happens when you use a JAK inhibitor or biologic agent or a TNF inhibitor. It looks like in those cases, patients were more likely to be ambulatory.

So those are on a biologic or JAK. Fifty percent of the hospitalized patients were on a biologic or JAK, but of the ambulatory patients, seventy six percent on a biologic or JAK. If you look at TNF inhibitors, nearly half the patients who are ambulatory were on a TNF inhibitor, whereas twenty one percent of the people hospitalized were on TNF inhibitor. I look at this and say those who are on more advanced therapies may be better controlled or more likely to be managed in an outpatient ambulatory fashion. But the takeaway point of this article from Haberman et al.

Was that baseline biologic use was not associated with worse coronavirus infections. There are a few articles in Alzheimer's rheumatic disease and in J Room, looking at what happens when our patients have been, affected by this. This particular report I'm showing you from Matthijn, in adult rheumatic disease looks at seventeen patients with the coronavirus infection and what happened to them. So these seventeen patients, they were all on hydroxychloroquine, and they've been on hydroxychloroquine for an average of seven point three years. These people were pretty severe lupus patients.

They had the antiphospholipid syndrome in four, see chronic kidney disease in eight, twelve on prednisone, seven on immunosuppressants. Again, fourteen were admitted to the hospital, thirteen of the seventeen had viral pneumonia, eleven respiratory failure, five cases of ARDS, and three renal failure. So when they looked at these patients, eight of them, they had actually blood levels of hydroxychloroquine done and showed that they had, plasma concentrations ranging from two fifty four to 2,095, a mean of six forty eight suggesting they had good, healthy, hydroxychloroquine levels, meaning they weren't undertreated. All the patients either had their immunosuppressant drug interrupted or stopped. Sixteen of the patients, had no signs of lupus activity.

And again, fourteen were admitted, and at the period of follow-up, they had thirty six percent had been discharged, fifty percent were still hospitalized, and two had died. The bottom line of this report was, yes, even lupus patients on hydroxychloroquine can get severe COVID infection and fourteen percent of them may in fact die. Another report from Italy was actually a survey. This is from Tomolleri and colleagues reporting on a survey data of one hundred and seventy two patients with large vessel vasculitis. And they asked them, you know, have you been affected?

How you've been affected? Have you actually got the infection? Turns out there was only four infections, two of whom were hospitalized, two of whom were treated as an outpatient, all did well and recovered. But what they did notice was, and it's unclear whether they had a higher rate, a lower rate. Again, it's a random sampling, but they did good.

But they did note a fair amount of problems with the lockdown on delivery of care. So their infusions were affected, their care was affected, but no one relapsed during this short period of observation. Six were unable to reach the infusion centers, two had to change to another subacute treatment, two went to another hospital, two were postponed. All in all, about ten percent of patients actually had inconvenience and their care being affected by the COVID lockdown. An interesting report this week from Gold et al in medical MMWR from the CDC looked at COVID infected patients in Georgia in April 2020.

The main purpose of this report was to say, hey, guess what? One in four hospitalized patients with coronavirus had no recognized risk factors for severe COVID, meaning they weren't obese, they weren't diabetic, they didn't have heart disease, lung disease, etc. But again, twenty six, twenty eight, thirty percent, overall, almost over one in four patients, had no background comorbidity. But they also did list, those, what was the number of people who had rheumatic or autoimmune conditions, and overall it was low. It was two point six percent of the patients, very low in the eighteen to forty nine, age group at one percent, higher five percent in the fifty to sixty four group, and in the elderly 65 was only one point seven.

We're not very well represented among patients who are severely affected with the coronavirus. Another report came out this week in arthritis research and therapy. Vincent et al did a meta analysis of what happens when you stop biologics. This is important because all the guidelines are saying continue the hydroxychloroquine, maybe you should hold the biologic. Is there a consequence to that?

I worry about that. What I think I'm going to show you and say here is that patients who are well controlled and are on therapy seem like they're doing fairly well in either avoiding or tolerating this infection. And I worry about patients who stop their biologics, where they will go out of control, inflammation will rise and their outcomes will be poor. Well, this particular meta analysis, it has nothing to do with COVID, by the way, it's just their RA and their SPA patients, two thousand two hundred and sixty patients, all of whom were in remission. The RA patients, most of whom were RA, had a DAS ERP of 1.6 to 2.3.

Their VAS dies were less than two. The infection rate in those who tapered and stopped compared to those who were usual were not different. They were basically non inferior to each other. But in fact, those who taper had a lower infection rate, one point seven per one hundred patient years looking at serious infections, and two point six per one hundred patient years for those who were on usual care and maintain their biologic. So this says that, you know, you probably can get away with stopping the biologic without increasing the infection rate, and that may be okay to stop these drugs for people who you suspect as having the, coronavirus infection.

So, I want to remind you about the ACR guidelines that were published this week. Ted Nichols from Omaha was the lead author on that. You can find that in arthritis and rheumatology. Again, the guidelines say do not stop therapies in people who you're seeing, that you should deliver normal care as you normally would. You should continue the ACE and ARBs for hypertension.

You should not stop denosumab. You can extend it only as much as eight months. There's a serious downside to that. But for those who are COVID exposed or undergoing testing, you should continue the sulfasalazine, hydroxychloroquine, nonsteroidals, not sure what to do with the rest. And then if they are infected, you can continue the hydroxychloroquine, but stop sulfasalazine, methotrexate, leflinamide, immunosuppressants, JAKs and biologics.

You might could continue the IL-six inhibitor because not know what to do there. And for unclear reasons to me they say stop nonsteroidals, it doesn't make any sense. There's no good reason to do that. But again, who's really sick with a positive infection, you're probably not going to use nonsteroidals anyway. But I want to point out some other points that we get from the studies.

First off, the NIH guidelines on the COVID-nineteen infection say if you have mild, moderate or severe disease, there is no current recommended therapy, either antiviral or immunomodulatory for patients who have a COVID-nineteen infection. In this report, they do say there's no evidence favoring the use of hydroxychloroquine for prophylaxis or treatment of those who have the COVID-nineteen infection. If you're on steroids, you should probably continue it for chronic disease. Don't use steroids to treat COVID. There's no evidence that it works.

Use steroids to cover people in shock if that happens or use steroids for your protocol that you have locally in managing ARDS. Some centers do like that, some do not. So again, I want to show you some of the data on some of the drugs that, we use, and how they've been used in COVID, specifically chloroquine, hydroxychloroquine, IL-six, IL-one inhibition, JAKs, and colchicine. The VA trial, know, first there was this trial out of Marseille of 26 patients. I'm not covering that.

I talked about that past. It was a horribly flawed trial and it basically said, looks like hydroxychloroquine with or without azithromycin may lower viral titers or have more seroconversions. But it was a badly done study. This particular hydroxychloroquine VA trial is a preprint. It's not been peer reviewed yet.

It's a retrospective study the VA experienced of comparing those who are on hydroxychloroquine to those on hydroxychloroquine plus azithromycin to those with no hydroxychloroquine. Again, these are COVID patients on these drugs for whatever reason. This is just sort of an analysis of data. The primary endpoint was whether they died or they needed mechanical ventilation. And it turns out that they had worse outcomes, worse COVID outcomes in patients who are on hydroxychloroquine.

So for instance, if you look at deaths alone, there's twenty eight percent of those on hydroxychloroquine died. Twenty two percent of those on hydroxychloroquine azithromycin died versus those not on hydroxychloroquine, eleven percent. Again, these are people within the VA system. There was, about the same ventilation across the board. Bottom line was a two point six fold higher risk of death with hydroxychloroquine.

They summarize this by saying the findings from this retrospective study suggest caution when using hydroxychloroquine in COVID infections. And the last study on hydroxychloroquine is this COVID study from Brazil. It's an interim analysis of eighty one patients. They were supposed to enroll four forty four patients with severe coronavirus infection. They stopped at eighty one when they noticed that there were eleven deaths.

This particular trial, patients were either given high dose, chloroquine six hundred milligrams bid for ten days or a lower dose of nine hundred milligrams on the first day and then four fifty every day for four days. Of those in the hydroxychloroquine high dose group, they tend to be older and tend to have twelve percent versus zero in those on the usual dose and then have more cardiovascular disease, eighteen percent versus zero percent. And these patients, you know, the bottom line here is will these drugs cause QT prolongation? They looked at that. In fact, it was higher in the high dose group, nineteen percent versus eleven percent in the low dose group.

But you know what? If you had QT prolongation, it was not associated with death or cardiovascular outcomes or torsades de pointe arrhythmias, which you might expect. It turns out that the people who died were more likely to die who those who had preexisting cardiovascular disease. And the people who died were also those who were older. So it may not be the cardiac effects of chloroquine.

It may be that chloroquine in elderly people with cardiovascular disease may not actually be a good idea. They said skepticism towards the enthusiastic claims about chloroquine use should perhaps curb its exuberant use. So should you use these drugs? Again, there's a potential for their use because in vitro studies have shown that they may have antiviral activity to the mechanism by which they work. And the Marseille study said you might have more seroconversions.

And you know what? The ACR and the NICE guidelines and the German guidelines say it's okay to continue hydroxychloroquine. The problem is that there are randomized controlled trials of antimalarials that failed in treating influenza or in preventing influenza, failed in treating dengue, chikungunya and Ebola. That there have been studies showing no benefit in HIV and there's one study showing a worsening of chikungunya virus infection, at least acutely. There's studies from China showing no differences in seroconversion rates if you were on hydroxychloroquine or not.

The Brazil study said you had more deaths on chloroquine, and the VA study said they also had more deaths on hydroxychloroquine. The NIH guidelines are more judicious, saying there's no evidence favoring their use at all. And recently, Health Canada and the FDA came out with a recommendation, a communique to the public saying don't use this drug unless you're part of a clinical trial or in a hospital, but to use it outside of that would not be a good idea. Now, IL-six inhibitors are in the news. We had a report this week about the two studies with IL-six inhibitors.

The idea is that you want to prevent, especially the cytokine storm, which can be a terminal event. Cytokine storm, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, or the hemophagocytic syndrome, HLH, they're all the same thing. It's a cytokine storm induced by CD8 cells unable to lyse APCs and turn off an immune response. Instead, you have a sustained and amplified immune activation with a lot of cytokines being produced, typified or driven by gamma interferon, and that leads to the cytokine storm, high fevers, hypotension, altered mental status. You should suspect this when people who are not doing too bad develop pancytopenia, severe LFT elevations, and hyperferon anemia.

Other markers here are high LDH, high CV25, soluble CD25, high IL-six levels, very high CRP, a dropping, SED rate because they have lower fibrinogen levels. They can develop a coagulopathy with D dimers. This has a high mortality when it happens. The treatment of the cytokine storm syndrome is so far IL-six inhibitors. But there are trials with IL-one inhibitors and emapalumab and other drugs that are usually used to treat macrophage activation.

So let's talk about IL-six inhibitors. As you know, there is a cardiac issue here, or is there? Up to twenty percent of patients on IL-six inhibitors may develop a hyperlipidemia, but yet the observation has been so far that there's been no increase in MACE levels. I'll point to two different studies, one a claims data analysis, and two the INTRACT trial. Tocilizumab against, itanoscept followed for three years, no increase in MACE events, despite lipids going up.

So that's a concern. But IL-six inhibitors may very well work. And, this is really based on a study that I've shown here from China, Zhu et al, twenty one patients with severe hospitalized ventilator assisted COVID-nineteen patients, And they all had high CRPs, high IL-six levels. But when tocilizumab was given, guess what? They all rapidly improved clinically.

Their fever went away. Their labs got better. And nineteen out of twenty one were discharged within two weeks. Very impressive. But now we have clinical trials going on.

Regeneron and Sanofi issued a press release of one of the early results of their cerulimab study. Three fifty eight hospitalized patients with COVID. They were either given placebo or high dose ceruleumumab four hundred milligrams or usual dose two hundred milligrams. And they compared the outcomes in a phase two trial of those who had severe disease, which is about twenty eight percent, or those with critical disease, about half the patients, critical being they were intubated in an ICU. Now, while many these patients were discharged, eighty percent, the ten percent did die in this study and ten percent were hospitalized.

Table I'm showing you on the right here shows that the primary endpoint, was met with sorrelimab. Placebo patients were only able to, reduce their CRP in only twenty one percent reduction with placebo. But with cerulimab, it had a seventy seven percent to seventy nine percent reduction, and that was the primary endpoint. But when you looked at other things like death, or ventilator assistance, it's really different. So placebo patients, fifty five percent of them died.

If you were on ceruleumumab, forty six percent, died if you had, severe disease. But if you had critical disease, only thirty two percent died or on a ventilator, suggesting that only the critical patients are going to benefit from getting, the high dose of, ceruleumin. So again, a preliminary result, it's got a lot of holes in the way it was written up. I'll just say it's encouraging data for ceruleumumab. More encouraging data came about this week with a report from France where one hundred and twenty nine patients with moderate to severe COVID-nineteen pneumonia were treated with, standard of care plus or minus tocilizumab.

The primary endpoint that they looked at was either death or ventilation at day 14. And the bottom line was no numbers, no data. They say that there were significantly fewer deaths and requirements for ventilator assistance in the tocilizumab group, suggesting that that and so they're gonna write that up. It might look good. We need to see that.

But this is very preliminary data, and it's hard to say where this goes. I think this seems to work because really we're not treating coronavirus, we're treating the damage and preventing the damage incurred by the severe inflammation that may occur. IL-one inhibitors are in clinical trials, both anakinra and canakinamab. There was a report also this week from the Astopolis in Annals of Rheumatic Disease. It's case report.

And it says a 70 year old female with a five year history of Cryopieren associated Periodic Syndrome, or CAPS, that was proven by genetic testing. She was being treated with canakinumab, one hundred and fifty milligrams every eight weeks, last given on March 15. Ten days later, the patient develops a fever of 37.5 malaise, had a known exposure and a positive SARS CoV-two test. White count was 4.3, CRP was high at nine milligrams per deciliter. Twelve days later the patient had her symptoms resolved and the SARS CoV-two test was now negative suggesting that our patients with inflammatory disorder on a biologic may have a less a more benign course and less, and certainly not a severe outcome.

This is encouraging, but it's an N of one. It's hard to say what it means. Lastly, an interesting report about baricitinib. You know, baricitinib may work because it's been shown to inhibit AAK1 and G associated kinases, two important regulators of endocytosis. And endocytosis is the means by which the coronavirus is going to bind to the ACE two receptors and via endocytosis gain entry into the cell where it's going to do its damage.

Moreover, a JAK inhibitor has the advantage of, decreasing, cellular activation and cytokine signaling and overall decrease in inflammation. So we have one trial that's out there. And that trial is called, it's authored by Cantini, also came out this week. They treated 12 patients, 12 consecutive patients who were hospitalized with a COVID and they were COVID positive, hospitalized with x-ray proven pneumonia. 12 consecutive patients were treated with baricitinib four milligrams a day plus antiviral therapy with ritonavir, lopinavir for two weeks.

And then the outcomes are measured at two weeks. They have a control group where the 12 patients that were treated before these 12 baricitinib patients were enrolled. And those people were given the same antiviral therapy, but they were getting hydroxychloroquine four hundred milligrams for two weeks. Again, there was really no SAEs in this trial. There was one patient who had really high LFTs in the two fifty to three hundred range presumed to be due to antiviral therapy.

So what happened when you got hydroxychloroquine or baricitinib on a background of antiviral therapy? Guess what? The hydroxychloroquine control group did not do well. They had no significant changes in their clinical status or their labs, but the baricitinib group had significant improvement in CRP levels, in, lymphopenia, improved. ICU admissions were zero in the baricitinib group and four in the control group.

Discharges were higher in the baricitinib group, fifty eight percent versus eight percent in those in the control or hydroxychloroquine group. Encouraging first step data that should drive, the use of this in future trials. Colchicine, as you know, isn't going into a clinical trial that was started by the Montreal Heart Institute, UCSF, and NYU. They're going enroll 600 patients. The idea here is give this to early patients.

Treat them with a zero point five milligrams BID for three days and then QD for twenty seven days. You had to have the coronavirus plus, you had to, here we go, you had to have a high risk factor. That's age, diabetes, lung disease, heart disease, CAD, fever, dyspnea, pancytopenia, any risk factor. They want to see at that point whether you may have a better outcome. Their primary endpoint is going to be death or hospitalization, at the end of the month.

They expect the results of this to be done by September 2020. There have been reports in the literature we covered this week about B cells maybe being active, that patients with A gamma globulinemia seem to do well. They have no B cells and no immunoglobulin. They seem to do well. Whereas CVID patients with sort of dysfunctional B cells, they didn't do well.

They had more severe courses. What about TNF inhibitors? There's a report in Lancet from Mark Feldman and Tiny Mani and colleagues suggesting we should be studying TNF inhibitors in patients with the COVID infection. Look for that report in Lancet. And then lastly, Amgen announced yesterday that they're going to be doing studies of opimilast, the PDE4 inhibitor in patients with, COVID infection.

As you know, it's approved for use in psoriasis, psoriatic arthritis, Behcet's. How this works? It doesn't work very well. It's kind of a mild drug, very safe, works in some people really well, doesn't work in a lot of patients. But you know, how it works mechanistically, you know, it decreases intracellular cAMP, cyclic AMP, but, does it actually affect cytokine production?

I think it actually has a lot of effects on neutrophils and chemotaxis, and that may be one reason why it may work, especially if used early when the innate immune response is kicking in. We'll have to wait and see where that goes. Anyway, I think that our patients are at low risk, And I think they're at low risk because we have them well controlled. If you look at this, graphic by Randy Cron and Wynn Chatham from UAB, it suggests that by bolstering their immune response in those with autoimmune disease and controlling their disease, and by doing replacement in those who have immunodeficiencies, you allow your patients to better manage infection. So, and maybe they're primed to better manage infection.

Maybe that's why we're seeing good outcomes. This is my hypothesis. We need more data. Hopefully our big room registry of COVID patients will tell us more in the future. Anyway, that's it for this week on the RheumNow podcast.

Go to the website. You can watch this, find some of the links that I have in here, and tune in next week for more information from RheumNow. Take care. Have a good week.