With rituximab-treated patients having an elevated risk for severe COVID-19 and a reduced likelihood of responding to vaccines, Sebastian Sattui and David Jayne discuss how these challenges can be addressed and explore the future role of the drug for the treatment of rheumatic diseases (13:17).
00:00 Introduction to the speakers
00:26 The current situation with rituximab and COVID-19
01:32 Considerations for patients with rheumatoid arthritis
02:46 Considerations for patients with ANCA-associated vasculitis
06:02 Optimizing response to vaccines
07:38 Other interventions to reduce COVID-19 risk or severity
09:40 Balancing disease control and infection risk
11:50 Concluding remarks
Sebastian Sattui: My name is Sebastian Sattui. I'm an assistant professor in the University of Pittsburgh School of Medicine in the Division of Rheumatology. I'm a rheumatologist, and I'm also the Director of the Vasculitis Center here, at the University of Pittsburgh.
David Jayne: Hi, My name is David Jayne. I'm actually a nephrologist originally, but I've specialized in vasculitis and lupus for a number of years. And I'm a professor in the Department of Medicine at the University of Cambridge in the United Kingdom.
Sebastian Sattui: So we're here to discuss a little bit about the impact and how this care for patients who are receiving treatment for rituximab has been impacted by the COVID-19 pandemic. And what we know at this point, two years after, and this has been certainly stated and reassured by multiple observational studies and even newer, larger studies using large claims databases in different countries, is that patients with rituximab are at an increased risk for both severe complications of COVID-19 infection, including death. And this has certainly impacted the care of patients who are on this medication and depend on this medication for the treatment and control and remission of their diseases.
And the use of rituximab, as we need to remember, it certainly expands from the treatment of conditions, such as rheumatoid arthritis, to the use of other conditions, such as vasculitis, particularly ANCA vasculitis, where induction and maintenance is also used. With regards to how rituximab is used in patients with rheumatoid arthritis, it is the use and the continued use of rituximab is something that needs to be continuously discussed ongoing with patients, and it's part of a shared decision making process.
The I guess-- not to minimize the problem, but the advantage that is present in the care of patients with rheumatoid arthritis, is that there's certainly a larger amount of actually other potential therapeutics that can be used to actually control disease activity. And that is certainly an advantage in the care of patients with RA. That being said, it might not be an option for all patients. And this is where kind of optimizing vaccination and other measures need to be taken into account, since as we can see in clinical practice, a lot of patients have not responded to previous treatments and rituximab has actually been the game changer. So that is one specific situation in the context of RA, but it's certainly not necessarily a simple solution either.
David Jayne: Yeah, so moving to ANCA vasculitis, the introduction of rituximab really has been game changing. But we have to remember that the trials that were done did not show a convincing superiority for rituximab, it showed essentially equivalence to cyclophosphamide. Although we do now feel that rituximab is the preferred agent for proteinase-3 ANCA patients where it probably is superior and certainly increases the ability to stop steroids, which is of great benefit to patients.
And in North America more than Europe, rituximab is now far-and-away the dominant induction immunomodulator used for ANCA-satiated vasculitis. I think we still have some concerns in patients with severe nephritis as to whether rituximab is an effective enough treatment. The more recent data concerns use of rituximab as a maintenance agent and we have two reasonable-quality studies now showing that rituximab is better to azathioprine, regardless of your induction immunosuppressive and regardless of whether you are treating new-onset or relapsing disease.
And giving patients rituximab every 6 months has proven to be very attractive therapy for patients. They're off most oral, if not, all oral medications. They come to the clinic once every 6 months, get their rituximab. That was fine until two problems came along. The first is immunodeficiencies, secondary immunodeficiencies, to which ANCA vasculitis patients seem particularly susceptible, and then the second is COVID.
And as Sebastian has mentioned, rituximab increases the risk of hospitalization compared to other DMARDs. And it pretty well flattens the antibody response to immunization. So this has been a bit of a challenge for us. I think we have slightly reduced our use of rituximab as primary induction. We're using a little bit more cyclophosphamide. But for remission maintenance, we're now tending to give rituximab as needed and then put more weight on monitoring good communication with the patient and treating at time of flare.
The problem with that is if your health care system is not really working smoothly, which is what happened in the first lockdown, you're missing the early signs of flare. And then patients are suffering. So I think we are treading this slight tightrope at the moment about trying to get patients adequately protect against COVID and trying to prevent relapse.
Sebastian Sattui: And I think that's pretty important because as Professor Jayne is explaining, this goes far beyond also the communication. And there's the logistics and now, the impact of health care, and access to health care within the pandemic that we keep struggling with. And it's still a big issue in health care systems worldwide. And so it's an ongoing discussion. It's very important to actually keep the communication ongoing with patients. With regards to vaccination, which there has been now-- at this point, we have data regarding kind of trying to optimize vaccination in patients who are receiving B-cell depleting therapies, and certainly the information that we have available now not only comes from patients with ANCA vasculitis or rheumatoid arthritis, but also there's some information coming from patients with multiple sclerosis, for example, that are also reliant on B-cell depleting therapy. And this is informing some of the guidance documents from entities, such as the American College of Rheumatology (ACR) and EULAR, is trying to find that sweet spot where you can delay rituximab and find a good moment where you can actually go ahead with vaccination.
And the data is pointing to trying to either delay past the 6-month cycle-- there's some studies. And this really varies, depending on which side you look into, but at least seven months or so out of the cycle, trying to actually look for a specific number, kind of B-cell reconstitution, which has been shown to be quite important for actually a good response to the vaccine.
There are some other studies that actually show T cell and CD4 counts as well as showing a way to ensuring a good response to the vaccine. Certainly, B-cell reconstitution is something that we tend to use a little more clinically and probably is something that can guide clinicians and patients into making the decisions of where the timing is. But I think the key part is that communication with patients and the close monitoring of both symptoms, in order to guide both therapy and also timing for vaccination.
The other important thing as well is that patients who are receiving or who still depend on B-cell depleting therapies in order to maintain disease remission, need to be prioritized for either early treatment in case of exposure and post-exposure prophylaxis as well as in some places, pre-exposure prophylaxis as well. Which is of course a difficult topic given the issues with availability and distribution of these medications. But I think from what we know now, is patients who depend on medications like rituximab need to be prioritized for these interventions.
David Jayne: Yeah, and I think this is where we're going to see practice change over the next 12 to 18 months. I think with the wider availability of monoclonal antibodies moving from therapy of COVID to prophylaxis of COVID, these patients with essentially secondary immunodeficient states, we're going to get put on long-term prophylaxis. And then we can treat their disease more effectively. In lupus, where we have essentially two biologics, belimumab and rituximab, we've moved very heavily away from rituximab into belimumab. And the data, although it's incomplete, suggests that belimumab does not have such adverse effects on vaccine responses or on hospitalization rates.
I think one of the other potential changes that's coming through from current trials may be synchronization of rituximab with belimumab. And we're doing a study in vasculitis at the moment. We're inducing with rituximab, and then we're assessing belimumab as a maintenance agent. Too early to say or to give any recommendations for practice but there's analogous work in lupus suggesting the same thing.
And that may be a way out of this repeated cycles of B-cell depletion blocking the antibody response. But as vasculitis doctors stepping back, really the crucial thing is control the vasculitis. And when you're faced with these competing challenges, that should take priority. And I'm not sure, Sebastian, whether it's fair to make the distinction with RA, but my impression with RA is you can more afford to wait for the joints to flare, and then treat, whereas with vasculitis, you really-- you often can't because if you miss the flares, bad things happen.
Sebastian Sattui: I think every patient is an independent discussion. And this of course-- every case is different. But certainly in cases of vasculitis, there could be potentially more to lose. And that's where prioritizing care. And as we know as well, active disease is not necessarily good for either the disease itself or even the risks that come with COVID and other infections, with the use of higher doses of prednisone and so forth. So I certainly agree with that.
David Jayne: One of the questions that comes up is whether we should move back to using oral immunosuppressants, like methotrexate or azathioprine, as remission-maintenance drugs. But the studies that have been done suggest that after rituximab induction, these drugs are remarkably inefficient. And relapses will occur. So we tend at least in vasculitis, we tend not to use them. Lupus is slightly different. In lupus, you're usually running a patient on a background immunosuppressive and putting the biologic on top, so it's a slightly different situation.
I think the other point that I would make, and this speaks to the issues about health care systems, is to extent the problems we have with primary care. So in other words, community care. And if patients are finding it harder to access the hospital, they're really then going to rely much more on the community care. And we are, if we're managing the patients by telephone to get all the lab results and assessments, the vital signs, and unfortunately, that's just not happening well, for lots of reasons. And that's a challenge, I think, for the future.
Sebastian Sattui: I think the pandemic keeps putting us in a point of taking us out of the comfort zones that we have reached. For the care of patients with vasculitis, rituximab is, as Professor Jayne pointed out, a big game changer. But now we need to try to find ways in order to either keep our patients under control or actually protect our patients as well, and keep working towards good access to healthcare good communication, and multidisciplinary care for our patients, whether they have vasculitis or any other rheumatologic disease or autoimmune condition. And for patients on immunosuppression for sure.
David Jayne: I think the challenge is how we organize our services. We are the specialists in managing these patients, and it's our job to reconfigure our services in the face of these changes. I think we do have new therapies coming along. Sebastian mentioned the breadth of therapies in RA. We do have new therapies coming along in ANCA vasculitis, avacopan or Tavneos, we're not quite sure what its role is going to be. Meanwhile, we've got the tools that we've got, and we just have to learn to use them as well as we can in the current climate.
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