- 18 Aug 2020
- 22 min
- 18 Aug 2020
- 22 min
Should patients with rheumatic disease stop taking immunosuppressants during the COVID-19 pandemic? To find out, David Liew interviews rheumatologist Philip Robinson and infectious disease physician Evan Bursle. Read the full editorial in Australian Prescriber.
Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed, and free.
In a pandemic, we often think about the people who are at greatest risk, and what we can do for them. When any infection comes along, it's natural to think about what it means for people receiving immunosuppressive medications for autoimmune disease. As a rheumatologist and clinical pharmacologist, this personally goes through my mind a lot, but it's clear that this is a question that affects a large number of people in our society. And it's particularly relevant when we think about the possibility of what living with COVID in this world might look like.
So what do we do for people with autoimmune disease? Should we worry? And is it different depending on what immunosuppression they're getting? I'm David Liew, your host for today's podcast, and I'm here with two experts from the University of Queensland. Associate professor Philip Robinson, a rheumatologist from the Royal Brisbane and Women's Hospital, and at the University of Queensland, is also the chair of the Steering Committee for the COVID-19 Global Rheumatology Alliance, meaning he has been directing efforts internationally to get data-driven answers in this space.
To give us the flip side of this as well, we've got Dr Evan Bursle, an infectious diseases physician at the Princess Alexandra Hospital in Brisbane, and also a microbiologist at Sullivan Nicolaides Pathology. Together, they've written an early release article in Australian Prescriber out on August the 18th 2020 about the management of autoimmune disease during the COVID-19 pandemic. Philip, Evan, welcome to the program.
EB: Thank you very much.
PR: Thank you.
So around the country, around the world for that matter, there are clinicians who treat autoimmune disease patients who are saying, "What should we tell our patients? What should we do for our patients?" And we have these patients with autoimmune disease who are often pretty scared understandably, given they have something which changes their immune system. So maybe I can ask both of you in turn. So Evan, maybe I can start with you. As an infectious diseases physician and microbiologist, how do you see this paradigm with these people with immunosuppression?
EB: I think the easiest way to start thinking about it and reducing and addressing these patient’s anxieties is to reduce their risk of infection in the first place. And a lot of our article does focus on simple measures that patients can take themselves to reduce their risk of contracting the infection in the first place. And I think that really has to be at the forefront of everyone’s mind. If you can prevent infection, then obviously you don’t even have to worry about the downstream effects of what might happen with your risk in the context of your immunosuppression.
So things that are crucial for that are things like maintaining excellent hand hygiene, maintaining physical distancing when appropriate, and following all the good public health measures that are really well promoted at the moment in the context of this pandemic. Staying home when you can and when it’s appropriate, avoiding large crowds, using masks outside and in contexts where it’s recommended. So I think all that’s very crucial before you even think about what your risk might be from your immunosuppressive medication.
Mm-hmm (affirmative) It’s the simple stuff which can make for a real difference in a pandemic like this, I guess.
EB: Absolutely. And it’s the same theme for lots of infections, but obviously it’s heightened in the current circumstance. And the things that patients might have to do might differ dependent on the local epidemiology for COVID in their area. So things might be a little bit different in terms of the steps people on immunosuppressive medications should take, whether they’re living say in a hotspot in Melbourne, for example, at the moment to living say in perhaps outback Queensland, where there’s a very little risk of acquiring COVID in their community.
Mm-hmm (affirmative). So Philip, maybe I can switch to you at this point to ask, well, in terms as a rheumatologist, do you think about the different immunomodulatory therapies that you use in different contexts in terms of infection? Where does that sit? And once we’ve kind of got past the simple stuff, do you change the way you approach things?
PR: Well, I suppose the first thing to think about is it’s not a one way street when you think about being on immunosuppression, because you’ve clearly made a decision to go onto immunosuppression based on the risks and benefits that you feel for the disease. So whether that be rheumatoid arthritis or whether that be ANCA vasculitis, those things really play into it. So part of what you want to think about is also the reasons why you’re even on the medication that you’re on and the complications and adverse events that you’re trying to think about.
I suppose the first thing, and this applies to everyone who’s on medication that might affect your immune system is that there has been very universal opinion amongst experts in that if you are not infected, you should not change your therapy. And part of that comes down to the fact that you’re on that medication for a reason, and depending on the local characteristics that are important in your area and the sort of the public health aspects of it, your risk of an adverse event from discontinuing medications may well be, and it’s probably much higher than your risk of an adverse event from actually contracting COVID-19.
So it has really been universal that you shouldn’t be discontinuing medications based on the fact that you’re worried about what the outcome might be. And if that’s a concern for you, and obviously every situation is different, then I think it’s important that you actually talk to your doctor about that, because your doctor has a really good understanding about the potential adverse events that might come from discontinuing some medications versus others that patients might not fully appreciate.
EB: If I can just add. And I think it’s important as clinicians to portray what the risk might be for the patients, and put the risk in context. I think in this pandemic, fear and anxiety spreads really, really easily and you get it every day, even from other clinicians in fact. And perceived risk is often a lot higher than what actual risk might be. So if you can put into context perhaps the prevalence of COVID in your particular area for the patient to help potentially allay their fears about continuing their immunosuppression for what presumably is an excellent reason to be on in the first place, as you mentioned Phil, then that can help in those discussions with the patients.
So, I mean, for context for example, I guess our prevalence of COVID in Australia is really far less than 1% of the population. So we’re looking at probably even less than 0.1%, and this is very different to what’s happening overseas, where there has been up to sort of 10% of the population.
I mean, all of that seems really important for our frontline clinicians. I mean, there are hundreds of thousands of Australians who are taking some form of immune modulating therapy, and I’m sure a large proportion of those would have gone to their local GP, to their local pharmacist, and asked questions when the pandemic started about what they should be doing about their medications. So I mean, I think I draw a lot of reassurance as I’m sure a lot of people do from that, and especially thinking about patients who we’re going to start on immunomodulating therapies, and we’ve got a choice potentially of which agent we choose.
So how do we assess the infection risk overall, especially keeping in mind that maybe infection risk for bacterial infections might not be the same as for viral infections, and that within viral infections the risk between different types of viral infections might be different? Is that the case for COVID?
PR: Yeah, it’s interesting. So obviously there’s some good association between certain immunosuppressions and risks for certain infections. For example, TNF inhibitors, a strong risk of TB reactivation, rituximab, a risk of reactivation of hepatitis B. So these are things we always screen for to reduce the risk of that happening in susceptible populations. Viral diseases outside of hepatitis B perhaps, and respiratory viral illnesses haven’t been subject to that level of knowledge about particular risk previously. And the predominant one we see from a pandemic point of view or a yearly epidemic point of view is influenza. And that’s a little bit different because we do have a vaccine that’s efficacious to some extent any way that can reduce patient’s risk.
So we haven’t, prior to this pandemic, been able to draw on a lot of information about what the particular risks might be from particular immunosuppressive agents. And I think that’s really the usefulness of the data collection and study that Philip’s team has done in terms of teasing out what really are the actual risks for patients on these medications.
So, I mean, that’s the kind of thing we’re dealing with right now in that we’ve got to try and rapidly make some data-driven decisions and how we’ve never seen SARS-CoV-2 before I guess there’s some precedents from SARS-CoV-1 and other coronaviruses, but they don’t necessarily translate as well. It sounds like that we really need to rapidly get real-world data in place. I mean, that’s the kind of stuff that you’re doing at the moment Philip, isn’t it?
PR: Yeah, that’s right. We are just about to recruit our 4,300th patient across the global registry. So we’ve been able to accumulate quite a bit of real-world data. Of course it has its limitations because it’s clinician-inputted data, but certainly we’ve seen consistent signals for some agents across multiple different registries. And I suppose the important ones to think about are glucocorticoids. So prednisone, we’ve seen increased risks for poor outcomes including hospitalisation and death in COVID-19 global rheumatology lab registry. We’ve also seen that in the SECURE-IBD registry.
So I think that’s a pretty consistent signal that we’re seeing. We’ve also seen out of the IBD registry information that would suggest that sulfasalazine might be an increased risk for poor outcomes. Now, at least in the published data to date, it’s a little bit mixed, but certainly I’m aware of other data that might also support this too. So I think we need to be cautious thinking about sulfasalazine too. And on the flip side of that, I think there are some agents that also look like they may well be protective. Now again, we don’t have good controls to look at the data, and so this is all relative. But at least from the point of view of biologics, there’s data that looks like TNF certainly doesn’t seem to increase your risk, and may in fact decrease risk of poor outcomes. And that probably relates to the severe hyper inflammation state that is often driven by cytokines. And so agents that target things like TNF probably are able to dial down there and decrease the complications that come from the hyperinflation that really drives the very poor outcomes that we see in COVID.
So before we go on, let me get the 1000 pound elephant in the room out of the way. Let’s talk about hydroxychloroquine very briefly. Is there something that we need to be worried about starting patients on? I think there are a lot of people who have seen a lot of the talk about adverse events from hydroxychloroquine and COVID, and are potentially concerned about starting it at this point in time. And on the flip side, there are some patients who might not ordinarily have considered hydroxychloroquine for their disease and are seeking it out. What would you say to them Philip?
PR: Well David, you'll be well aware that we've been using hydroxychloroquine in rheumatology for longer than probably you and I have been alive. I think it was recognised during the Vietnam war to be useful in autoimmune diseases, particularly rheumatoid. So from that point of view, it has had a long history of very safe use. Now it’s been recognised when you use it in very unwell patients at a very high dose, it seems to have negative cardiac outcomes, including prolonging your QT, especially if you combine it with other QT prolonging agents.
So because of this discussion, patients have come out and said, "What is this drug I'm on? This is a problem for the heart." And I said, "Well look, we've been using it very safely in patients that have had rheumatic disease on the doses that we use, which is generally maximum 400 mg. And we've been using it for a very long time." But if you go and look in the literature, including very recent literature, it does prolong QT by itself. And then when you use it with azithromycin, for reasons that I'm not a 100% clear about, but anyway, if you do use it with that drug, you will prolong the QT even longer, even further.
So I think that this is a tale of two separate uses, and one is a relatively safe use in rheumatology, and the other is when you give it to a critically unwell person with other agents who are often elderly and have other comorbidities.
EB: I think it's really interesting what you said, Phil, because David introduced me being perhaps on the flip side, an alternative view, but I think for most of this discussion, we firmly believe the same things. But it's interesting you end up having to discuss with your patients that are on hydroxychloroquine the safety of it in light of this poor level of publications that have come out in relation to hydroxychloroquine, and in the context of COVID. Because we do see the flip side there as we tend to have to deal with people wanting to use hydroxychloroquine for COVID, and you guys have to deal with patients potentially thinking about stopping it having seen adverse outcomes from these trials. So I find that really fascinating. I hadn't actually considered that your patients might be worried by the hydroxycloroquine trials.
PR: Yeah. And they say, "Are you putting me on this Trump drug? Is that what you're doing? Do I want that?”
It's really hard to be able to shape this public discussion in a nuanced way about something like hydroxychloroquine. And I guess we've got to be the light of sensibility to our patients. Well let me put another one to you, which has been a little bit in the media. So Philip mentioned glucocorticosteroids, and there has been a lot of talk about dexamethasone from the RECOVERY study looking at potential benefit from dexamethasone, something which is being used in clinical practice at the moment in COVID-19 infected patients.
So Evan, do you think that it's hard for people to resolve that result with the results about people on steroids being at greater risk of contracting COVID-19? And do you think that that signal about corticosteroids was a predictable one, as far as COVID-19 is concerned?
EB: I’m not sure if anything is particularly predictable at the moment with COVID-19, and we’ve seen contradictory studies in flu, for example, with the use of steroids. But I think that the RECOVERY study’s result was really robust, and most sensible places have moved to instituting that as a therapy in patients where it’s indicated. I don’t really think it is inconsistent with what has been seen in Phil’s registry though, because we know that not everyone benefits from dexamethasone. So the RECOVERY trial showed benefit in patients that required supplemental oxygen, but in fact, no benefit for patients that didn’t, and in fact, a trend to worse outcome if you used it in the early stages in patients that did not require supplemental oxygen or invasive ventilation.
And so it’s difficult to extrapolate that on patients that are having it prior to being infected, but you could think that they’re sort of analogous to those that are on it in the early phase, where there wasn’t a benefit. And I guess it’s not known whether the dexamethasone effect applies to all other steroids. It may well, but I don’t think we know that from the data we have as yet.
Mm-hmm (affirmative). I’m sure there is a lot more nuance to drag out. I mean I think probably one area where it gets a bit complicated is when we think about the biologic and targeted synthetic agents that Phil and I prescribe to our inflammatory arthritis patients amongst others. Actually Evan, I might ask you this first. Do you think that, in terms that we’ve got multiple different agents targeting different parts of the inflammatory response. Do you think it’s plausible that there might be differences between different agents? And would we expect to see signals when it comes out in the real-world evidence?
EB: I think conceptually there are some potential differences and there has been a lot of interest in things like tocilizumab and some TNF inhibitors, and there’s trials involving anakinra as well in terms of switching off that hyper immune response, which causes a lot of tissue damage and potentially pulmonary damage. And so conceptually there potentially is some differences in those. I think you can’t really rely on those concepts translating into actual benefit. I think we’ve seen that with tocilizumab. There was a lot of hope that that might be really useful, but recent information that has come out of the trial from the drug company there has shown they weren’t meeting their primary end point for mortality. So conceptually there is some differences, but it’s hard to really predict how that will pan out in properly done randomised controlled trials.
Yeah. So Phil, I mean, thinking about that, do you think that it’s as likely to be a difference in terms of COVID-19, both in terms of getting it and in terms of severity between all the different biologic agents?
PR: Yeah. Look, I think there will be. We’ve already seen early signals of that in the published data from the rheumatology registry. As our numbers increase, I have little doubt that we will see differences between them because we actually have a relatively broad range of targets. We’ve got co-stimulatory inhibition, we’ve got IL-6, and we’ve got IL-6 receptor, and then we’ve got IL-6 molecule, and we’ve got a fusion protein TNF, and we’ve got monoclonal TNF. And then we’ve got B cell depletion. And then, although not so widely used in Australia, but we’ve got harder on Bliss inhibition. We’ve got belimumab data out of the US and out of Europe.
So look, I think I am confident to say that we’re going to see differences, and that’s going to come out when we’re able to publish our much larger data set which we’re currently analysing. And then it’s going to be interesting because these drugs have different half-lives. Rituximab obviously has got a very long half-life compared to an agent such as etanercept which would last for a week. And then potentially we’re going to have to think further and try and increase the nuance of our approach to these agents.
And I wonder if we’re actually going to see. So to give you some context, the American College of Rheumatology’s advice is when people become infected is to stop all agents. But perhaps as part of a shared decision making process, you can carry on with IL-6 inhibition. Now I wonder if in time with the data, there are going to be other things added to that, other agents that’re potentially shown to be, maybe IL-6 is going to be taken off that list. I think as the numbers increase, and ours is certainly not the only group thinking about this. There is no doubt that the companies are thinking about this from a safety point of view because this pandemic ain’t going away anytime soon. So I think that in a matter of time, we’re going to have lots of different sources of information and that will help to guide differences between biologics.
So it sounds like, while we can make educated guesses about potential risk and benefit in both the situation leading up to a potential infection of enduring infection based on the immunology and based on what we know about the diseases we’re treating, but also COVID-19 in general, we can make best guesses. But in reality, we are also going to need to see that real-world data to be able to know where the risk lies. It’s a complicated situation.
PR: Yeah, absolutely. And as we talked about right up front, these things are all within a context of what's happening around you. Your considerations about what to start and when are very different if you've been community transmission free for a hundred days like New Zealand was up till recently as if you're sitting in the Austin Outpatient Clinic in Melbourne right now. So it's tempting to think about odds ratios and agents and mechanisms of action, but they all sit in a much wider context that I think is really important not to forget.
Absolutely. And I think like Evan said at the beginning, we really just can't forget the simple stuff that is really what's going to get us out of this mess in the first place. So thank you very much to both of you for joining us today. It has been a fascinating conversation, and I'm looking forward to seeing how this all evolves in the next few months.
PR: Thank you.
EB: Thank you very much.
The views of the hosts and guests on this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm David Liew. Stay safe, and thanks for joining us once again.