David Karp, MD, PhD: ACR Hydroxychloroquine Suggestions for Rheumatology and COVID-19

March 30, 2020
Hydroxychloroquine has been in the news a lot lately due to its potential affects on patients with coronavirus disease 2019 (COVID-19). The findings of recent reports, however, have unclear methodologies, giving way to new research needing to be conducted. What's more, this medication, which is typically used for patients with rheumatoid arthritis and lupus, is already in short supply.

David Karp, MD, PhD, president-elect of the American College of Rheumatology (ACR) discussed what an appropriate hydroxychloroquine trial would look like, alternate treatment options, and how rheumatology experts should approach their patients during this time.



Editor's note: The following interview has been lightly edited for style, length, and clarity.

HCPLive: I'm here today with David Karp, MD, PhD, president-elect of the American College of Rheumatology. How are you today?

Karp: Considering the circumstances, I'm fine and good afternoon. I'm happy to be talking to you.

HCPLive: I wanted to just start off by having you discuss the ACR recommendations for hydroxychloroquine. Can you explain the reason behind the suggestions and how they were established?

Karp: Well, to answer your second question, the leadership of ACR and several of its members have put together a taskforce over the past 2 weeks to address this issue. There have been some findings from in-vitro experiments done in tissue culture that suggests that hydroxychloroquine can lower the level of infectivity of SARS-CoV-2, the virus that causes COVID-19 disease. Again, those are done in tissue culture. And were very striking results—those were published earlier this year.

Then more recently, there have been some studies out of France that have suggested that hydroxychloroquine could be beneficial. We have some concerns, as do many scientists about some of the methodology in those studies. But together, it suggests that there might be a reason to look at this drug for treating patients with COVID-19.

That said, the evidence is still slim, and we believe that there needs to be done quick and well-designed clinical trials to establish the real role for hydroxychloroquine in COVID-19. At the same time, we have many patients who rely on these medications and have relied on them for years or decades in some cases, and hydroxychloroquine has proved to be the most safe and effective medication for them.

So, our position is that we want all of our patients, as well as the public at large, to have access to this medication, as it is shown to be effective. To that end, we are working with our advocacy groups and trying to learn from pharmaceutical companies how they can provide stocks of hydroxychloroquine that they already have on hand. Some companies have offered to donate hundreds of millions of doses for this purpose, as well as to increase their ability to produce this pharmaceutical.

HCPLive: You mentioned some data findings and the French report specifically. Government officials and President Donald Trump have all mentioned findings by Gautret and his colleagues. What about the study and findings made the report so unclear or murky?

Karp: To be brief, the studies are not well controlled, and that's always a concern when you're looking at a drug for a new indication. We certainly understand the ethical conundrum that researchers find themselves in.

The best possible way to test hydroxychloroquine or in fact, any other drug that's being looked at as a treatment for COVID-19 is to do a placebo-controlled study where somebody gets the medication and another patient doesn't get the medication. That's very tough to do and causes a lot of anxiety amongst patients and doctors as well, in a situation as severe as COVID-19.

But others, including some very prominent ethicists, have said that it would be unethical not to do a placebo-controlled trial because without that, we really won't know whether these drugs work. And I'm speaking not just about hydroxychloroquine, but any other drug that's being tested for COVID-19. We need to think about that. And there are some other clinical trial designs where everybody in the trial can get a medication, but not every patient gets the same medication. And at the end, we sort out what works best. It's not as precise as a placebo-controlled trial. But I think in the case of a pandemic, such as this, we need to do our best job.

HCPLive: The guidelines mentioned the importance of the drug for patients with SLE. How does hydroxychloroquine benefit this population?

Karp: It's been shown for probably decades now—we've been using hydroxychloroquine since the 1950s, but we have studies that go back well past the 1990s—that show that hydroxychloroquine decreases the rate of flares and organ damage in patients with lupus. It's the only drug that's been shown to decrease mortality in lupus.

That said, we all know that the rate of flares increases slowly when patients stop their hydroxychloroquine. And not every patient will flare. But we want to reassure our patients that we are working for them and with them, and even if they can't get the hydroxychloroquine at their local pharmacy on the first try, there's probably time for us to look for other sources and even think about other medications.

HCPLive: What mechanism of action overlaps exist between hydroxychloroquine and potential COVID-19 treatment?

Karp: Well, hydroxychloroquine concentrates in an intracellular compartment called the endosome. And the endosome is slightly acidic, and it uses that slight acidity to help it degrade pathogens such as bacteria and viruses that invade our bodies. It also uses that acidity to help signal by creating inflammatory cytokines, particularly the ones called type 1 interferons. And we believe that those interferons are part of the reason that people have the signs and symptoms of conditions like lupus. Hydroxychloroquine raises that acidity a little bit or raises the pH, decreasing the acidity, and makes those endosomes less likely to signal and the cells less likely to produce those inflammatory molecules.

So, what I tell my patients and is that hydroxychloroquine sort of turns down the volume on their immune system, but doesn't immunosuppress them, and allows them to fight off bacteria and viruses.

Now, by the same token, SARS-CoV-2, the virus that causes COVID-19, gets into the respiratory epithelial cells using those same endosomes. And it uses that acidity to help cause a conformational change in the virus that allows it to fuse with the cell membrane and get it into the cytoplasm and replicate and kill the cell.

And so, the thinking is that hydroxychloroquine, by altering the acidity of the endosome, can prevent some of that fusion of the virus into the cell. There's also a thought that by just decreasing the immune system a little bit, hydroxychloroquine may provide a benefit to the later stages of COVID-19 where we believe that the patient's immune system is actually attacking its own tissue in too great a way.

HCPLive: There’s already a shortage of hydroxychloroquine as it is. In lieu of even more fills of this medication due to COVID-19 priorities, how will patients be treated?

Karp: We want every patient to talk to their rheumatologist or rheumatology health professional and have an action plan ahead of time. The options differ for different diseases. If a patient has rheumatoid arthritis, for example, the use of hydroxychloroquine is usually as part of a well-balanced cocktail of medications and there may be the opportunity to substitute another oral medication or even switch to an injectable medication at this time. That can be difficult sometimes with insurance companies creating barriers to patients switching medications. The American College of Rheumatology is working with our advocacy groups to try and reduce some of those barriers to rheumatologists in order to get substitute medications to their patients.

With lupus, it's a little bit of a different story. There are only 4 drugs approved by the FDA for the treatment of lupus and they go back pretty far. They include aspirin, prednisone, hydroxychloroquine, and more recently, the drug belimumab, which is an infusible or an injectable medication. We are fearful that a lot of patients and doctors are going to have to use medications like prednisone, which is a great drug for reducing inflammation in the short term, but we know in the long-term, even at modest doses, leads to irreversible organ and tissue damage in our patients and causes a significant amount of morbidity. In particular, it increases the patient's risk of infection to ordinary bacteria and viruses. So, we would be concerned that if a patient had to be placed on a different medication than hydroxychloroquine, then their risk of getting another infection might increase as well as may complicate their recovery from COVID-19.

We have always been borrowing drugs from other disciplines to treat lupus and in particular the transplant community where we've used medications like azathrioprine, mycophenolate, or tacrolimus. These are all used off-label. They are not indicated for the treatment of lupus, but many rheumatologists will use them because there are no currently approved drugs that work as well as some of these others in dire situations. I'm assuming that that's what we will have to turn to knowing that these options are going to be less safe and perhaps less effective than hydroxychloroquine for our patients.

HCPLive: Are there any other tips for rheumatologists or experts in this field for how to approach treating patients at this time?

Karp: I think the most obvious one, and the one that we all need to think about, is that the best outcome for any of our patients is to not get COVID-19. So, at this point, social distancing is very important and paying attention to proper handwashing and all the other things that we are supposed to be doing.

I tell my patients that I really don't want them to get the disease. That will make everything a lot simpler. That sounds pretty trivial, but it's really the most important thing we can do right now for treating patients.

Again, I think every patient who is concerned now should have a conversation with their rheumatologist or rheumatology health professional and talk about what the options are and have a have a battle plan going forward.

HCPLive: Thank you so much for your time today. Do you have anything else you would like to add?

Karp: No, I just wish that you and all of your viewers stay healthy.
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