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The Role of Immunosuppressives in Breakthrough COVID-19 Infections Among Rheumatic Patients

In This Article

  • Rheumatic patients who are fully vaccinated for COVID-19 are having a disproportionate number of breakthrough infections
  • Laboratory-based studies have described a blunted immune response in rheumatic patients on certain immunosuppressive medications
  • Massachusetts General Hospital rheumatologist Zachary S. Wallace, MD, MSC, has helped develop and report clinical correlates of low antibody levels among this patient population
  • Dr. Wallace discussed the implications for the care of rheumatic patients taking immunosuppressives that may blunt the vaccine response

The efficacy of COVID-19 vaccines in the general population is well-established. Among patients with systemic autoimmune rheumatic diseases, however, many questions remain.

Zachary S. Wallace, MD, MSc, a physician in the Division of Rheumatology, Allergy and Immunology at Massachusetts General Hospital, has been tracking breakthrough COVID-19 infections among vaccinated patients with rheumatic diseases in the Mass General Brigham system. He and Mass General Brigham colleagues have observed that those with breakthrough infections among this patient population are having an inadequate immune response to the vaccines. Their findings complement a recent paper published in the Annals of Internal Medicine that describes the blunted immune response to vaccines in rheumatic patients on certain immunosuppressive medications, such as tumor necrosis factor inhibitors and methotrexate.

"This and other laboratory-based studies showed that some rheumatic patients were not having a great vaccine response, but there were no clinical correlates," Dr. Wallace says. "We've been developing and reporting clinical correlates of low antibody responses and other blunted immune responses. That seems to be reflected in what we're seeing clinically in terms of breakthrough infections, especially in some patients on medications that tend to blunt the immune response to the vaccine."

Since the start of the pandemic, Dr. Wallace has been studying COVID-19 in patients with rheumatic diseases in partnership with Brigham and Women's Hospital rheumatologist Jeffrey A. Sparks, MD, MMSc. The two have led efforts to identify all such patients throughout Mass General Brigham and both are part of the COVID-19 Global Rheumatology Alliance, which is collecting information pertinent to rheumatic patients with COVID-19.

Before the vaccines were made available, Drs. Wallace and Sparks focused on whether underlying disease and disease-modifying anti-rheumatic drugs (DMARDs) increased rheumatic patients' risk of contracting COVID-19 and of having worse outcomes.

"We started to identify subgroups of patients who did much worse than the general population—specifically, those who were receiving stronger immunosuppressives that affect the body's ability to respond to COVID-19." Dr. Wallace says. "For instance, patients who used rituximab and other B cell depleting agents."

Earlier this year, examining the vaccine response of rheumatic patients became the top priority for Drs. Wallace and Sparks. Prior research had shown that some immunosuppressives used to treat rheumatic disease blunt the immune response to influenza and pneumococcal vaccines.

Drs. Wallace and Sparks suspected a similar dynamic could be at play with rheumatic patients and COVID-19 vaccines. "That led us to use the data sources we've been assembling through this large cohort to start systematically identifying and characterizing breakthrough infections and seeing if the patients having breakthrough infections are the same ones we know have a poor immune response to the disease," Dr. Wallace says. "And that is exactly what we've been seeing."

Dr. Wallace was the corresponding author of a letter published in the Annals of the Rheumatic Diseases in September 2021 describing breakthrough infections in rheumatic patients—the first case series published on the topic.

"We observed that the patients who were having a blunted immune response in laboratory testing were the same patients in whom we're seeing these breakthrough infections—that is, patients who were on certain DMARDs, such as rituximab, methotrexate or mycophenolate mofetil," Dr. Wallace says.

Implications for Clinical Care

Dr. Wallace had these recommendations for rheumatologists and other physicians with rheumatic patients who are on immunosuppressives that may compromise the vaccine response:

  • Continue to stress to vaccinated patients the importance of practicing risk-mitigation strategies, such as wearing masks in public, socially distancing and avoiding large indoor gatherings where the health and vaccination status of others is unknown
  • For patients who are unvaccinated, try to understand and address the reasons for their hesitancy. If they agree to get the vaccine, Dr. Wallace says, "you may need to hold off on their medication for a little bit around the time they get vaccinated, if their disease activity permits that, or time the vaccine for before they're due for the next treatment"
  • A patient who has been or may have been exposed to someone with COVID-19 or who is diagnosed with COVID-19 should contact their providers immediately and be prioritized for monoclonal antibody therapy, which has been shown to reduce the risk of severe outcomes from COVID-19. "Whether post-exposure prophylaxis or as treatment if symptomatic, it's important to get them in early," Dr. Wallace says. There may be a role for pre-exposure prophylaxis in certain immunosuppressed patients in the future
  • Given the lack of a clinical correlate, Dr. Wallace advises against measuring post-vaccine antibody levels or T-cell responses. "It's hard to know what to make of the data we have thus far, and we don't want to falsely reassure patients who may in fact still be at high risk for COVID-19 despite being vaccinated," he says
  • Many vulnerable rheumatic patients are frightened and continue to remain socially isolated. Take the time to discuss and understand how the pandemic has affected them. Suggest safe ways they can interact with others and, if you have concerns about their mental health, encourage them to seek counseling

Clinical Trial on the Effects of Booster Doses

Dr. Wallace is the site principal investigator of an ongoing clinical trial studying the effects of COVID-19 vaccine boosters in patients with autoimmune disease and poor response to initial vaccination. The investigators are assessing how temporarily stopping the medication being taken for an autoimmune disease affects the vaccine response.

Currently, the trial is open only to patients who have not received a vaccine booster. Dr. Wallace hopes the trial will soon be expanded to include patients who have already received their booster dose but had an inadequate response; these patients will be given the option to receive a second booster dose.

"I think there's a lot of excitement and enthusiasm about trying to figure out what vaccine series we can use in our patients that will get them to have an appropriate immune response," Dr. Wallace says.

Learn more about COVID-19 research at Mass General

Refer a patient to the Division of Rheumatology, Allergy and Immunology

Related topics


Kristin M. D'Silva, MD, and Zachary S. Wallace, MD, MSc, of the Rheumatology Unit, report that 10 out of 13 patients (77%) who had a rheumatic disease and COVID-19, and subsequently underwent SARS-CoV-2 antibody testing, had detectable antibodies.


In a registry study of 2,869 patients with rheumatoid arthritis and COVID-19, Mass General Brigham researchers and colleagues found that use of rituximab or JAK inhibitors at the time of COVID-19 onset was associated with worse COVID-19 outcomes than for patients using tumor necrosis factor-α inhibitors.