Jeffrey Sparks, MD, MMSC, and Alfred Kim, MD, PhD, on COVID-19 Vaccines for Patients With RMDs

In this podcast, rheumatologists Jeffrey Sparks, MD, MMSc, and Alfred Kim, MD, PhD, discuss how recent developments in COVID-19 vaccine research and policy may affect patients with rheumatic and musculoskeletal diseases.

Jeffrey Sparks, MD, MMSc, is an assistant professor of medicine and associate physician at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. Alfred Kim, MD, PhD, is an assistant professor in the division of rheumatology at the Washington University School of Medicine and director of the Lupus Clinic.

TRANSCRIPT:

Welcome to another podcast from the Rheumatology and Arthritis Learning Network. I’m your moderator, Rebecca Mashaw. Today, Dr Jeffrey Sparks of Harvard Medical School and Brigham and Women’s Hospital in Boston, and Dr Alfred Kim, from Washington University and director of the Lupus Clinic there, are going to talk COVID-19 and patients with rheumatic diseases.

Dr. Jeffrey Sparks:  Hello, my name's Jeffrey Sparks. I'm a rheumatologist at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. I am here with Dr. Alfred Kim. If you want to introduce yourself, Al.

Dr. Alfred Kim:  My name is Al Kim, an adult rheumatologist at Washington University School of Medicine in St. Louis, Missouri, USA. I also founded and codirect the Lupus Clinic here.

Dr. Sparks:  Great. We want to talk about all things COVID vaccination and rheumatic diseases. Plenty to talk about with that. I guess the most current news is related to both the FDA approval, full approval, for just the Pfizer vaccine as well as an extension of the Emergency Use Authorization for immunocompromised patients for a third dose.

How have both of these news, that came in a pretty similar timeframe to each other, how has that affected your patients, Al?

Dr. Kim:  I think especially the additional dose extension of the EUA has been very important. Our group, along with several other groups, including this really nice paper that came out in Lancet Rheumatology from Laura Boekel, who's a Dutch rheumatologist there, has shown that there are various immunosuppressive medications that are used in rheumatic diseases that can definitely decrease antibody responses to SARS-CoV-2 vaccinations. The need to be able to maintain higher levels of responses appears to correlate with higher levels of protection. And so the best way we can do this probably is going to be through providing this additional dose of a SARS-CoV-2 vaccine.

I think fom a patient perspective, this has been met with much enthusiasm of my patients with lupus. I would say several dozen have already gotten an additional dose. We still do have a handful of people that haven't gotten vaccinated at all simply because of fear of altering their disease activity or inducing a flare, which is something we can discuss about in a little bit.

Dr. Sparks:  I'll just add to that that this happened on a Friday afternoon and I remember opening my inbox for my clinical email, and I probably had 15 patients who got it that weekend. At least here in Boston, there's been incredible uptake.

The timing, obviously, with the Delta variant and community levels being high is really important. I'm not sure how much that went into the reasoning, but certainly, it seems the antibody levels wane, and now is the right time to have as much protection as possible. I think that was the right move.

What I've been fielding most questions about are medication changes. As you probably know, the ACR recommendations were a bit more definitive than I anticipated, in that they recommended holding basically every medication, at least the immunomodulators and immunosuppressants that aren't biologics or anticytokines; they said to hold those for 2 weeks after the third dose of the vaccine to really optimize vaccine response.

Some of these patients that got the vaccine right off the bat didn't even have time for the ACR recommendations to come out. Many of them didn't have a chance to talk to me to try to figure out what to do prior to that third dose. That's been interesting, navigating this wave of the third dose of the vaccine.

Dr. Kim:  Holding the medicines was interesting. You had tweeted this out seconds after the new guidelines were released about how this is a little bit confusing, because for the original series of vaccinations, for dose 1 and 2 for the mRNA vaccines, the holding of medications weren't necessarily as strongly recommended, if at all, for some of the medicines.

This was much more broadly applied for the third dose. I'm looking at Jeffrey Curtis' tweet from 5 days ago. He says, "But if holding helps improve booster response even a little bit, give people their best chance to respond. Also, remember, guidelines prize simplicity if possible."

I think there's another caveat here on top of simplicity and optimizing conditions to be able to maximize immune responses is that, remember, of course, the first 2 doses are spaced weeks apart, which means you're going to have to have 2 periods of holding, or have 1 very long prolonged period of holding, which may really promote worsening disease activity during that period.

Again, this is a data-free zone still, but again, these theoretical risks, the task force has done a good job. It's a really hard job to do, because they have to speculate on a lot of things in order to provide some actionable guidance.

Dr. Sparks:  Well, if I remember your seminal preprint in this area of research— are we allowed to say that it'll be out very soon, hopefully by the time this podcast is out?

Dr. Kim:  By the time this podcast is out, it would have broken press embargo. Yes, we're OK to discuss it.

Dr. Sparks:  The Annals of Internal Medicine, so congratulations to you and all of your collaborators.

Dr. Kim:  Thank you.

Dr. Sparks:  I think in particular, one thing that I've been trying to follow is, how much do glucocorticoids impact the immunogenicity of the vaccine? I feel like it's been a little bit in conflict. Just curious what you're telling your patients about steroid dose around vaccination and what the research has shown related to glucocorticoids.

Dr. Kim:  This has been all over the place. Just from our own experience, based on what we publish, which is not a large N of people for glucocorticoids, it's going to be somewhere around, I believe we had, something like — I'm looking right now — probably about 17 people. We found that even people on low-dose glucocorticoids had blunted or absent responses. We also had some people on low-dose glucocorticoids that had good responses, and then we have some people with high-dose that also had good responses.

This sits in contrast most specifically with Julie Paik's data from Johns Hopkins University that showed that people who are on glucocorticoid monotherapy all had excellent responses. It was the people on glucocorticoids with other medicines, particularly rituximab, which is already known to blunt responses, along with mycophenolate, another serious offender of poor vaccine responses. It's that mixture with glucocorticoids that then dropped responses.

Neither of us were able to report that triangulation of that, the concomitant medication use with dosing and response. Again, our cohort has tripled in size, if not more, since the paper. I think Julie's group has also increased substantially. We may end up needing to combine forces to answer this question about glucocorticoids.

As a result, essentially, what I've been guiding people is that, "If tolerated, we'll try to wean your glucocorticoids as low as possible or stop it for a week or 2." Again, these are all estimates and somewhat guesses on our end. Then, restart them if necessary. Again, this is a challenging area right now because of the data's a little bit all over the place.

Dr. Sparks:  I'll also mention that Al is a coauthor on the initial Global Rheumatology Alliance Vaccine Survey results. As part of that, we did assess for patients' willingness to want to hold medications. And actually patients were, by and large, very willing to hold medications temporarily if it meant that it might improve the vaccine response. The one medication that didn't follow that line were glucocorticoids. Probably because, I'm imagining, many patients have attempted weans and they already know what happens when they fall below the dose they're at.

That's just an interesting aside. That paper, hopefully, will be out within the next couple of weeks as well.

Dr. Kim:  Congratulations to you, Jeff, for that wonderful work.

Dr. Sparks:  For both of us as coauthors.

Dr. Kim:  You've done, obviously, some wonderful work, not only in terms of risk factors for more severe outcomes with COVID-19, but as we'll bring up later on, you have that wonderful recently accepted preprint that is looking at adverse outcomes in the vaccinated immunosuppressed people. We'll talk about that in a second, though.

Dr. Sparks:  Should we talk about CD20 inhibitors? Obviously, a major finding from your paper, probably not terribly surprising. Although, I have to say, having used these drugs for many years and how many vaccines I've been giving patients on rituximab and seeing the dismal immunogenicity responses, what are you doing with your patients on rituximab or other B cell-depleting therapies?

Dr. Kim:  To summarize the data, first of all, being on a B cell-depleting agent, especially recently, and then getting vaccinated, pretty much destroys any attempt at an antibody response. Obviously, this makes a lot of sense. B cells become activated, they'll differentiate into antibody-producing cells or secreting cells. Obviously, then, you get your humoral response from that.

Our data along with numerous other groups have shown that essentially, there's a window of about 6 months post-B cell-depleting therapy administration, and then vaccination where you will not mount responses. In other words, if you had your last dose of B cell-depleting agents, say, back in June, 2 or 3 months ago, the chances of you getting a response now if you got vaccinated is quite low. If you're beyond that 6-month window, let's say you got vaccinated back in, say, February, then your chances are going to be higher.

This has thrown a huge wrench, because other than that, I perceive B cell-depleting therapies as quite safe and very effective, particularly for a fair amount of my lupus population. Even though it's not FDA-approved to do so, we do use a fair amount of it.

This is throwing into question about, what are we doing with this and vaccinations? Even though we know that in the past, that flu vaccinations, again, show this poor response within this 6-month window post-B cell-depleting therapy administration, this is something that we try to build into the calendar, but we never measured postvaccination flu responses the way we've been doing with SARS-CoV-2 vaccines.

This is important, and there's good data from a preprint from Thomas Dörner’s group in Germany that showed that it's the presence of peripheral B cells in the bloodstream that seemed to correlate the best with a detectable humoral response. That, again, makes a lot of sense.

This is something that I'm still unpacking, because it's counter to how I want to use B cell-depleting agents, which is a lot. Now, it's making me re-examine the type of people that I need to use this type of therapy in, which is unfortunate, because, again, I perceive it as very effective for a lot of diseases.

Dr. Sparks:  What's the latest on the T cell response? There's a lot of hope that even though the antibody levels aren't going to go up high, that maybe there's some other arms of the immune system that might compensate for that.

Dr. Kim:  There are several preprints, one from Amit Bar-Or of Penn along with John Wherry. I believe there's another one from England. I have to double-check. There are a few reports that are showing that T cell responses do occur.

They are a little bit different in people who have antibody responses with B cell depletion therapy versus those that don't have antibody responses with B cell depletion therapy. Again, this is probably along the lines of that 6-month time period.

Bottom line is that the T cell responses in the people who have been B cell depleted and don't make any antibodies, they are different. They look like they don't quite make as many T cell subsets. They may not be as activated in certain aspects. They are qualitatively different.

I do think that the problem is that the issue with having data from Global Rheumatology Alliance along with your data with Zach Wallace is showing that B cell-depleting therapies definitely increase the risk of severe COVID and death from COVID-19. This makes the argument that, are T cells sufficient to drive protection? Again, these patients haven't been necessarily studied, B cell-depleted therapy patients with natural infection of COVID-19.

If we make an assumption that they are mounting some T cell responses, it is worrisome that maybe the T cells aren't as effective as we hoped and that antibodies may be a central key component overall.

Dr. Sparks:  To fill in a bit more detail about our paper, which will hopefully be in the Annals of the Rheumatic Diseases about around the time you hear this, it was just accepted for publication. It was a case series about breakthrough infections.

Certainly, this has been in the news a lot. In the general population, ours was the first to look within patients with systemic rheumatic diseases. It's tangentially related to the T cell discussion, because, first off, breakthrough infections do happen within rheumatic patients. I don't think that's that surprising, given vaccines are never 100% effective, and certainly, immunocompromised patients might do worse. I think the important part of it is that there were a number of serious infections, including deaths. The patients that unfortunately had the very severe outcomes of deaths, they were on the medications that the vaccine doesn't seem to produce antibodies to. We're talking rituximab, way overrepresented, but in our case series also the medications like methotrexate and mycophenolate mofetil.

I think this is a wake-up call that the antibody levels after the vaccine are certainly a surrogate, but we just happen to see the clinical outcomes in those very patients that this probably is a real risk as far as clinical outcomes.

Certainly, there's more to do related to that. How about anticytokines and vaccines, TNF inhibitors, IL-6 inhibitors?

Dr. Kim:  This has been probably the most interesting. I thought the responses would be much worse, especially with TNF inhibitors. So TNF knockout mice—these are mice that have been genetically modified so that they don't have any TNF alpha anywhere in the body—they had mounted pretty crappy B cell responses. There's a critical aspect of B cell responses called the germinal center that vaccines 100% leverage in order to generate maximal immunity. These structures are broken in TNF knockout mice.

I would have guessed that TNF and any sort of B cell response would have been really bad. All we found was about a two-and-a-half-fold reduction in antibody levels. Most people on anti-TNFs greater than 90% were able to generate an antibody response, which is extremely reassuring.

I think this highlights that there's a huge difference...Again, this is to the clinicians, because a lot of the bench scientists love to use examples from biology where you have a knock-in or a knockout mouse, where they make a lot of something, knock-in mouse, or they make nothing of something, a knockout mouse.

This does not represent what we see physiologically, even with a blocker like a TNF inhibitor. This is much more of a partial reduction in the activity and functional levels of TNF alpha as opposed to having it completely gone. This highlights that interesting subtle aspect between what we see in, say, animal models versus what happens in real life. Again, that's been reassuring.

This has been largely true with a lot of the anticytokine therapies we've been looking at is that the reduction in antibody responses have been quite modest. Certain ones, like the ones that block IL-12 and 23, they don't seem to have much effect whatsoever.

Some of these, we would have predicted. The TNF one, I always find surprising. Generally speaking, I think a lot of these are going to generate protective responses in these people.

Dr. Sparks:  We've been mostly talking about clinical management, clinical outcomes, some of the biology, and what's happening within the blood biomarkers.

Maybe we could talk a bit more about what might motivate patients who are on the fence about getting vaccinations, what your general perceptions have been as far as issues where patients are reluctant to get the vaccine, and how all of this complexity might be underpinning that.

What are your thoughts about that?

Dr. Kim:  If we table the entire misinformation issue—which is just catastrophic from day 1, going way back to hydroxychloroquine, our response as the hydroxychloroquine brigade, to try to give these patients a voice—if we ignore all of that, I think that largely, a lot of our patients have been very enthusiastic to get the vaccine. There are a few reasons why some of our patients have been hesitant from the beginning, one of which is that they're scared that this may cause a flare of their disease.

This is especially true in our lupus population here in St. Louis. The second is that they have this, sometimes, a philosophy where, "Well, if the vaccine is not going to work very well in me, then why should I get it in the first place?" In other words, there's a quantifiable harm here with an unclear benefit.

Again, this attitude has changed quite a bit recently with the emerging amount of data showing that most people can generate responses. That's obviously very important.

The third aspect is now related to this misinformation. There are still people that feel like they may get tracked by the government, and then they then proceed to go on Facebook to announce that. Obviously, there's a lot of tracking with Facebook, which is not something that they see eye and eye with us.

In terms of the flare issues, there has been good data, again, most recently by Julie Paik's group. Then, we're going to be having, hopefully, a paper coming out relatively soon led by Lianne Genzler and Monica Yang at UCSF looking at reactogenicity.

Largely, most people with autoimmune diseases don't flare. The flare rates tend to be around 2 to 5%. Laurent Arnaud in Strasbourg, France, had a nice VACOLUP study that got published in Lancet Rheumatology a few weeks ago looking at lupus patients specifically. It was like over 500 lupus patients, and he found a flare rate of something like 2.7% or something, very low.

The one thing that's also confusing to patients is how clinicians define flare versus how a patient defines flare. The major problem here is the systemic inflammatory events, whether that's going to be more diffuse arthritis with fever and diffuse myalgias, which doesn't necessarily reflect what happens with their disease.

Maybe they have lupus and they've never had arthritis, but if they happen to get that side effect, they think it's a flare. I totally understand why. For a clinician, researchers, we consider that more of an adverse event rather than a flare. In terms of adverse events, the rates appear to be similar to immunocompetent people also, which is, again, still reassuring.

These vaccines, again, are in the immunosuppressed community compared to immunocompetents. This is the reason why we continue to say these are both effective and safe.

Dr. Sparks:  I'll add that certainly, the Delta variant makes this a lot more of a pressing issue, and I'm hoping that will move the needle. I think it already has a bit. And the full FDA approval of Pfizer and hopefully the other vaccines soon. Certainly, businesses, employers— my employer recently required the vaccine. One of my patients that works here is finally going to get it based on it being fully FDA-approved and certainly wants to continue working for our organization. Those will help move the needle.

In particular, in rheumatology patients, I'm hoping that the simplicity of the third vaccine dose might make it easier for patients and providers. The initial recommendations were so complicated that it might have been that some patients were like, "Things aren't great with my rheumatic disease now. Let's wait till things settle down."

Now, with more waves of the Delta variant and such, you need protection right now. You can't wait down the road.

Dr. Kim:  Again, we're going to do an upper-level undergraduate deep dive into vaccinology right now.

The additional dose for the immunosuppressed not only helps restore antibody levels to levels that are going to be observed immediately after full vaccination, but our colleague at Wash U, Ali Ellebedy, has published numerous papers, beautiful papers that show that the exposure and re-exposure to vaccines helped diversify antibody responses.

This diversity is really critical, because even though we all have been immunized, let's say the immunocompetent people, say, you and me, Jeffrey, we got our vaccines back in January. We have protection against Delta, even though we got immunized against the common variant, because our immune system, particularly with that second shot, that's where the diversity of antibodies starts to explode and the antibody response blossoms.

It developed antibodies against Delta, even though Delta had never been observed on Earth before. This is the reason why these boosts and additional doses are so important, because it's not bringing the antibody's levels up, but the antibody quality, in terms of the type of things that it can bind to blossoms. This additional dose helps get that immune system to fully cover and anticipate even future variants that could be problematic. Again, this is a much deeper dive into some of the B cell biology and vaccinology that we think about.

At the same time, the bottom line is that the additional dose helps the response crystallize and become as full as possible.

Dr. Sparks:  You convinced me. I'm going to get my third dose.

[laughter]

Dr. Sparks:  Al, this has been a great discussion. We'll continue talking offline for sure.

Dr. Kim:  On Twitter.

Dr. Sparks:  On Twitter and online.

Dr. Kim:  @alhkim.

Dr. Sparks:  @jeffsparks.

Dr. Kim:  @jeffreysparks.

Dr. Sparks:  We should probably call it an afternoon here. Thanks again, and congratulations on the recent acceptance of your paper in Annals of Internal Medicine.

Dr. Kim:  Thank you, and congratulations to you, Jeffrey, for your recent acceptance into Annals of Rheumatic Diseases.

Dr. Sparks:  Thank you.

References:

Deepak P, Kim W, Paley MA, et al. Effect of immunosuppression on the immunogenicity of mRNA vaccines to SARS-CoV-2: A prospective cohort study. Ann Intern Med. Published ahead of print August 30, 2021. https://doi.org/10.7326/M21-1757

Cook C, Patel J, D'Silva KM et al. Clinical characteristics and outcomes of COVID-19 breakthrough infections among vaccinated patients with systemic autoimmune rheumatic diseases. Ann Rheum Dis. 2021 (In press). https://doi.org/10.1101/2021.08.04.21261618