Making Sense of the Connection Between Vaccines and Lupus Flares

In 1978, a team of Harvard Medical School researchers examined whether people with lupus responded to the iNFLuenza vaccine differently from the way a group of “normal” control subjects did. They looked at vaccine side effects, as well as post-vaccination lupus symptoms and autoantibody activity. 

“Symptoms after vaccination were somewhat more frequent in the [lupus] patients than in the normal subjects,” they reported. “However, all symptoms were minor and no major flare of illness occurred. No significant induction or increase of pre-existing autoantibodies among the patients was detected after vaccination.”

Flash forward almost 50 years, and the story remains much the same. When experts have gone looking for evidence that vaccines lead to flares among people with systemic lupus erythematosus (SLE), an autoimmune disease, they’ve usually found that a small minority of patients experience an uptick in disease activity, but that uptick tends to be mild or moderate. In many cases, it’s not clear that the vaccine is to blame at all.

“This is a big concern we hear from patients—whether their rheumatic disease will flare after a vaccine,” says Dr. Medha Barbhaiya, a rheumatologist and assistant professor of medicine at Weill Cornell Medical College and the Hospital for Special Surgery (HSS) in New York City. “What the data suggests is that most people do well, and severe flares are very uncommon.”

A vaccine-flare connection?

Intuitively, it makes sense that a vaccine—something that is designed to stimulate an immune response—may occasionally trigger a reaction in people who experience overactive or disordered immune activity, such as those with SLE. 

This intuitive connection has been explored in dozens of formal studies since that old Harvard Medical School analysis. Most have found some evidence that, yes, heightened disease activity or symptomatology can occur following a vaccine, but this happens in a minority of patients and tends not to be severe.

For example, a 2022 research review of 13 studies assessing the relationship between influenza immunizations and subsequent lupus flares found that anywhere from zero to 43% of lupus patients experienced a flare following the flu shot. Such a wide spread of findings makes it difficult to nail down the true frequency of post-shot flares. However, all of those studies agreed that severe flares were uncommon. One study found that 7% of patients experienced a severe flare, but all of the other studies found severe flares occurred in five percent or fewer of patients. 

These sorts of findings turn up again and again in analyses of vaccinations and lupus flares. For example, studies of flares among people with lupus receiving the human papillomavirus (HPV) vaccine have found that between zero and 13% of patients experienced a flare, but that flares tended to be mild or moderate. Another study, this one looking at hepatitis B vaccinations among people with SLE, found that 11% experienced flares, but this was similar to the number experiencing flares the year before (when they did not receive the hepatitis vaccination).

Such disparate data makes it difficult to identify the true risk of a flare following a vaccine. Further complicating matters is the fact that flares must be separated from adverse vaccine reactions, which are common among both people with lupus and the general population. For example, those who receive a vaccination may experience injection-site pain or soreness, headaches, fatigue, and other adverse reactions in the days following their shot. These reactions tend to be mild and temporary, but in rare situations can be severe.

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People with lupus are at risk for these adverse events just like anyone else. Are they at greater risk? That doesn’t seem to be the case. “There is no substantial evidence that patients with lupus have adverse events beyond what’s reported in the general population,” Barbhaiya says. 

What is it about vaccines that could cause a flare? Some researchers highlight the adjuvant components of vaccines as a likely culprit. “The adjuvants are used in vaccines to enhance the reaction against a virus or bacteria,” says Dr. Yehuda Shoenfeld, professor of medicine and chair for research of autoimmune diseases at Tel-Aviv University in Israel. “Subjects who develop SLE are, a priori, belonging to a group that are prone to a very high level of immune system reactivity, and so are likely to react more strongly to these adjuvants, which may induce flares.” 

There’s also some evidence that vaccines containing live, attenuated viruses may be risky for people with lupus. “In SLE patients taking significant immunosuppressive medications, live vaccines are usually avoided due to the risk of excessive viral replication, leading to severe and life-threatening infections,” wrote the authors of a 2021 research review in the journal Lupus. However, the use of live vaccines (such as for herpes zoster or polio) are no longer commonplace in the U.S., and so this risk is unlikely to be a consideration for most people with lupus. 

Taken together, the existing research suggests that flares are possible, but usually not severe. When one considers that people with lupus are often at elevated risk for severe infections, the benefits of vaccinations often outweigh the dangers.

“Vaccines have been proven to be safe in SLE,” says Dr. Michelle Petri, a professor of medicine and director of the Johns Hopkins University Lupus Center. 

Lessons from the pandemic

In 2021, Barbhaiya and colleagues, including Dr. Lisa Mandl, a rheumatologist and associate professor of medicine at Weill Cornell and HSS, conducted a study of COVID-19 vaccination responses among people with SLE. “The COVID pandemic offered this unique opportunity where we could assess vaccine outcomes in real time on a very large scale,” Mandl says. 

Their group’s study of 183 patients found that roughly 8% of SLE patients experienced a flare within two weeks of vaccination with one of the three available SARS-CoV-2 vaccines. “These results were very reassuring,” Mandl says. “Of the few who did report a flare, most were mild or moderate.” In fact, only one patient in the study experienced a severe flare following vaccination. Furthermore, most of the flares resolved themselves within seven days. 

“Our findings were consistent with some other studies looking at the effect of the COVID-19 vaccines on lupus,” she says. To her point, a study from a group of European researchers, the results of which appeared in the journal Lancet Rheumatology, likewise found that the number of SLE patients who experienced flares following the COVID-19 vaccine was in the single digits. Another study, this one from a French team, found that even among lupus patients with active SLE, the SARS-CoV-2 vaccines did not appear to cause a worsening of symptoms. 

While these studies suggest that, yes, some people with SLE may flare following the COVID-19 vaccine, it’s still not certain that the vaccine itself is to blame. “It’s tough to say for a fact that the vaccines caused the flares, or whether the patient would have flared as part of their normal disease course, because the percentage of those who flared was so small and there were also other potential factors we couldn’t control for,” Barbhaiya says.

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For example, she points out that, during the early stages of the vaccine rollout, when her study took place, some lupus patients were being advised to discontinue their immunosuppressant medications in order to ensure they would mount an appropriate response to the vaccines. It’s possible that the discontinuation of medication caused the symptom flares—not the vaccine. Sheer coincidence is also a factor: It may be that a person’s lupus flare just happened to align with their vaccination, and that the two had nothing to do with each other. 

While these factors can’t be ruled out, the consistency of the relationship between COVID-19 vaccines and lupus flares indicates that some low percentage of patients will experience an increase in symptoms. 

How could these vaccines instigate a flare? “Type 1 interferon is a cytokine thought to be involved in lupus pathogenesis and flares,” Barbhaiya says. “There was some concern that the SARS-CoV-2 mRNA vaccines could potentially induce this interferon and cause disease flare.” While that potential mechanism has not been thoroughly proven, researchers have found evidence that interferon activity may shift among people who experience flares following the COVID-19 vaccine. But again, that work found that just over one in 10 SLE patients (11.4%) experienced a flare following the vaccine, and within that group only about 1% of flares were severe. 

While flares don’t seem to be a major concern, experts point out that non-flare adverse events are commonplace among people with SLE—just as they are among the wider population. For example, some analyses found that three out of four people with SLE experience some kind of adverse event (AE) following the SARS-CoV-2 vaccination. But these AE figures were in line with the experiences of non-SLE patients receiving the vaccines.

A patient-by-patient approach

People with lupus may be at heightened risk for life-threatening infections, which means they may benefit more from a vaccine than those who have normal and Healthily functioning immune systems. On the other hand, the risk of flare activity following a vaccination appears to be a legitimate concern. Because of these comPeting considerations, lupus clinician-researchers say they often assess the need for a vaccine on a case-by-case basis. 

“By and large, I think physicians believe all their patients should be vaccinated, but personally I refer to each case individually—analyzing past History, and analyzing risk and benefit,” says Shoenfeld. 

Barbhaiya says she takes a similar patient-by-patient approach. However, she adds that she leans toward vaccinations in most situations. “We have substantial data showing that patients benefit from getting standard vaccinations—like flu vaccinations—so I think the risk-benefit is usually in favor of getting vaccinated,” she says.

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In an era of widespread vaccine hesitancy—or in some cases rampant misinformation—talking about vaccines with lupus patients can be a delicate proposition. Acknowledging and explaining the potential risks of a vaccine—risks that may include adverse reactions or flares—could ultimately deter some patients from going ahead with a shot. But experts say that being upfront about any risks—and also contrasting these with the well-studied benefits—is the most honest and often efficacious approach. 

Vaccinations save lives. They can help protect people with lupus from numerous life-threatening viral and infectious diseases. The research to date suggests that these benefits may all come coupled with some risks. Fortunately, those risks seem to be small for most patients.