Editor’s note: ACR on Air, the official podcast of the ACR, dives into topics important to the rheumatology community, such as the latest research, solutions for practice management issues, legislative policies, patient care and more. Twice a month, host Jonathan Hausmann, MD, a pediatric and adult rheumatologist in Boston, interviews clinicians and rheumatology professionals on important topics in rheumatology. In a series for The Rheumatologist, we provide highlights from these relevant conversations. Listen to the podcast online or download and subscribe to ACR on Air wherever you get your podcasts. Here we highlight , “B Cell-Depleting Therapies and COVID-19,” which aired on July 19, 2022.
The COVID-19 pandemic offered many lessons for rheumatologists in the use of B cell-depleting therapies and protection against this virus, according to Alfred Kim, MD, PhD, an assistant professor of medicine in the Division of Rheumatology, Washington University, St. Louis. Dr. Kim has done extensive research related to B cells and discussed B cell-depleting therapies and COVID-19 with podcast host Jonathan Hausmann, MD, for an episode of ACR on Air.
Early Pandemic Research
Dr. Kim
Dr. Kim said he had no expectations for how COVID-19 would affect immunosuppressed patients in early 2020. However, “I think by early summer, it was pretty clear that the presence of type 1 interferons, which are anti-viral cytokines, was critical in controlling that transition or the progression of COVID-19 into something more severe. Also, Akiko Iwasaki, PhD, at [Yale School of Medicine, New Haven, Conn., and colleagues] showed that the timing of when you started generating antibodies was also critical,” Dr. Kim says. “Both of these ended up as core correlates of protection—immune wise—to be able to limit the severity of COVID-19.”1
By the end of that summer, further research helped establish that rheumatology patients were at significant risk due to COVID-19, Dr. Kim says.
Dr. Hausmann
Dr. Hausmann notes that, at that time, some immunosuppressive medications were thought to increase the risk of developing COVID-19 or severe outcomes, but it was unclear which medications. Additionally, rheumatologists were concerned that if patients stopped immunosuppression, their underlying disease would flare—also not a good outcome in an infection setting.
Research during the pandemic from the COVID-19 Global Rheumatology Alliance, EULAR and others showed the biggest threat to these patients was likely B cell-depleting therapies for rheumatoid arthritis, lupus and multiple sclerosis.2
Despite some confounding research findings, Dr. Kim notes it was an exciting time to see immunity in action. “We are seeing in real time how this impacts not only autoimmunity, but also infectious threats and vaccine responses,” he says.
Understanding When to Use Therapies
Dr. Hausmann and Dr. Kim also note some of the contradictions surrounding rheumatic disease and COVID-19 therapy: Prednisone use may increase the risk of poor outcomes in COVID-19, but dexamethasone emerged as one of the first COVID-19 treatments. Anti-inflammatory drugs and cytokine inhibitors were in the mix to treat severe COVID-19.
“This was confusing when it came out, but I think right now what’s pretty clear is that with early COVID-19 infection, you need a robust immune response to try to control viral load, eliminate the virus and generate adequate immune responses,” Dr. Kim says. After the virus becomes severe, the immune response is pathogenic. “That is obviously the driving impetus of why immunosuppression is both a threat earlier, but also can be used as a treatment later on.”
This paradox was problematic to describe to regular people. “It was not something that was well elucidated or described by us as a profession. It led to a lot of confusion,” Dr. Kim says.
Expanded knowledge about COVID-19 led Dr. Kim to prescribe B cell-depleting therapy less frequently. This change led to some skepticism from certain patient groups, such as patients with lupus on rituximab who may have taken a long time to find the medication mix that put their disease in remission.
“I was a little surprised initially, but it makes a lot of sense when you think of it from their perspective and why they want to continue it,” he says.
Vaccination & B Cell-Depleting Therapies
Research revealed that patients on B cell-depleting therapy had a reduced response to COVID-19 vaccination, leading to concern.
“On Twitter, it became massive threads of people trying to figure out, ‘How do I mitigate this?’ or trying to take things into their own hands, which may have led to some people making decisions that we wouldn’t have necessarily advocated,” Dr. Kim says. “This includes trying to boost their immune system using whatever supplement they could find on the internet.”
The ACR recommended vaccines for every patient with rheumatic disease, including those on B cell-depleting therapies. Additional vaccine doses were recommended for some patients on B cell-depleting therapies and other immunosuppressive drugs.3
Mitigating Risk with Evusheld
One saving grace for immunosuppressed patients was Evusheld, a combination of two monoclonal antibodies (cilgavimab and tixagevimab) that were isolated from two patients who had convalesced from COVID-19, Dr. Kim explains.
The rationale for Evusheld is to limit the systemic spread of virus by administering highly neutralizing antibodies against the spike protein of SARS-CoV-2. Although it’s still possible to acquire a respiratory infection from COVID-19 after receiving Evusheld, the infection should be limited vs. systemic. The original FDA Emergency Use Authorization (EUA) for Evusheld focused on anyone who uses an immunosuppressive agent other than hydroxychloroquine, Dr. Kim says.
Overall, side effects with Evusheld were rare, with several thousand doses given at Dr. Kim’s university with no issues to his knowledge.4 Although an increased risk of cardiovascular disease may occur with Evusheld, this risk is more common in patients with prior cardiovascular events. “You can pick out these people in terms of risk factors and that discussion occurs, but it’s still quite low,” he says.
The emergence of the Omicron variant rendered Evusheld ineffective, and the FDA de-authorized the EUA for Evusheld in late January 2023 (after the release of this podcast). A clinical trial called SUPERNOVA is ongoing and is internationally examining the safety and effectiveness of an updated version of Evusheld, which can neutralize all the variants of concern currently circulating.
As findings from the COVID-19 pandemic continue to shape treatment for immunosuppressed patients, Dr. Kim says he’d like to see research expand in a few additional areas, such as additional dose responses in those on B cell-depletion therapy, mucosal immunity and impacted immunosuppression on durability of antibody responses.
Vanessa Caceres is a medical writer in Bradenton, Fla.
References
- Lucas C, Klein J, Sundaram ME, et al. Delayed production of neutralizing antibodies correlates with fatal COVID-19. Nat Med. 2021 Jul;27(7):1178–1186.
- Grainger R, Kim AHJ, Conway R, et al. COVID-19 in people with rheumatic diseases: Risks, outcomes, treatment considerations. Nat Rev Rheumatol. 2022 Apr;18(4):191–204.
- Bass AR, Chakravarty E, Akl EA, et al. 2022 American College of Rheumatology guideline for vaccinations in patients with rheumatic and musculoskeletal diseases. Arthritis Care Res. 2023 Mar;75(3):449–464.
- Alejo JL, Kim JD, Chiang TPY, et al. Patient-reported outcomes after tixagevimab and cilgavimab pre-exposure prophylaxis among solid organ transplant recipients: Safety, effectiveness, and perception of risk. Clin Transplant. 2023 Apr;37(4):e14913.
