New Research Shows That Rituximab and JAK inhibitors Are Linked with Worse COVID-19 Outcomes in Rheumatoid Arthritis

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The science is complicated because, well, the immune system is complicated.

It’s been suggested that biologic or targeted synthetic disease-modifying drugs (DMARDS) could dampen the body’s inflammatory response to COVID-19, which could actually lead to a less severe disease course. However, some DMARD medications might work in a way that impair the body’s natural immune defense against viruses.

Researchers analyzed medical data on DMARD use among people with rheumatoid arthritis at the time they got infected with COVID-19. They looked at the following medications or medication classes:

• Abatacept (Orencia)
• Rituximab (Rituxan)
• Janus kinase (JAK) inhibitors: a class of medications that includes baricitinib (Olumiant), tofacitinib (Xeljanz), and upadacitinib (Rinvoq)
• Interleukin-6 inhibitors (IL-6): a class of medications that includes sarilumab (Kevzara) tocilizumab (Actemra)
• Tumor necrosis factor (TNF) inhibitors, which served as a reference group: a class of medications that includes adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi, Simponi Aria), and infliximab (Remicade)

For classes, the different drugs were studied as an entire group rather than individually.

Researchers scored outcomes on a scale of one to four to mark COVID-19 severity:

1. No hospitalization
2. Hospitalization without oxygen needed
3. Hospitalization with any oxygen need or ventilation
4. Death

Of 2,869 people with rheumatoid arthritis taking biologic or targeted synthetic DMARDs when they developed COVID-19, there were:

• 237 on abatacept
• 364 on rituximab
• 317 on an IL-6 biologic
• 563 on a JAK inhibitor
• 1,388 on TNF biologic

Overall, 21 percent of the patients were hospitalized and 5.5 percent died.

The Effects of Rituximab on COVID-19 Disease Course

The authors found that taking rituximab was strongly associated with a higher chance of worse COVID-19 severity compared to taking a TNF biologic. In fact, 22 percent of rituximab users required hospitalization with oxygen or ventilation and 14.8 percent died — compared with 7.4 percent and 2.6 percent of TNF users, respectively.

Although rituximab patients were more likely than TNF users to have interstitial lung disease (ILD) (11 percent versus 1.4 percent) and history of cancer (7.4 percent versus 0.9 percent), the results were similar after the researchers excluded ILD or cancer from their analysis.

Rituximab is often prescribed to rheumatoid arthritis patients who haven’t improved on other biologic treatments.

“Rituximab is used in special situations in RA, particularly ILD or patients with a history of cancer, so we did some sensitivity analyses to try to protect against whether those special indications may have been driving the association — and we had similar findings,” says  rheumatologist Jeffrey Sparks, MD, a co-first author of the study. “However, we certainly recognize that the patients may be different since they ended up on this medication after trying many other medications. More studies are needed to make sure this is truly related to the drug and not related to the reason for prescribing it.”

Rituximab may be linked with worse COVID-19 outcomes even after accounting for comorbidities like ILD or history of cancer because it depletes B cells. These cells are an important part of your immune system, since they produce antibodies against antigens (for example, proteins from viruses or bacteria). Without B cells, your body may have a harder time fighting off COVID-19, which could lead to worse outcomes.

The Effects of JAK Inhibitors on COVID-19 Disease Course

Taking JAK inhibitors was also linked to higher chances of worse COVID-19 severity compared to taking a TNF biologic: Among JAK users, 15.3 percent were hospitalized with oxygen or ventilation and 7.1 percent died. JAK users were slightly more likely to be obese than TNFi users (15.1 percent versus 10.3 percent, respectively).

“JAK inhibitors do impair T-cell responses and have other effects on the immune system that may interfere with our ability to respond adequately to an acute COVID-19 infection,” says rheumatologist Zachary Wallace, MD, the other co-first author of the study.

Dr. Wallace notes that while the study’s rituximab observations have been observed in other studies, the finding that JAK inhibitors are associated with worse COVID-19 outcomes is more novel. Additional research is needed to better understand this observation.

“I think it’s also important to think about why JAK inhibitor exposure at the time of infection leads to worse outcomes, whereas we know from trial data that getting a medicine like baricitinib [a JAK inhibitor] to treat COVID hyperinflammatory syndrome could lead to better outcomes,” says Dr. Wallace. “It’s kind of a confusing story here, but it may be that if you’re on that medication at a baseline, it’s interfering with your body’s initial response to infection, and that’s more of a problem than anything else.”

Since JAK inhibitors were studied as a class, more data is needed on whether or not the association observed in this study is true of all JAK inhibitors.

“We know that JAK inhibitors differ from one another in their specificity for particular JAKs [Janus kinases, enzymes involved in inflammation], so we don’t know if this is truly a class-wide effect or if there are differences with specific JAK inhibitors,” says Dr. Wallace.

There was no association found between abatacept or IL-6 use with worse COVID-19 outcomes when compared with TNF users.

The Role of COVID-19 Vaccination

It’s important to note that the researchers did not specifically look at the effects of these medications on patients after they were vaccinated against COVID-19. The study was conducted from March 2020 to April 2021. While the researchers did not quantify how many patients were vaccinated, the majority of cases in the analysis occurred prior to the vaccine being available to most patients.

“Our study really only dealt with the outcomes of patients once they were infected, so it’s a bit of speculation as to how it applies to patients with vaccination,” says Dr. Sparks. “We’re recommending all of our patients get vaccinated, and there have been recommendations from the American College of Rheumatology about whether to hold medications temporarily. To me, for risk mitigation strategies, the first thing that comes to mind is vaccination.”

Research has shown that patients on rituximab have a diminished response to the COVID-19 vaccine. This would be expected since rituximab impairs the immune system’s ability to produce antibodies.

“Collectively, I think this is coming together as a story to say that we know rituximab interferes with antibody production, plus the depletion of B cells probably has other effects on the immune system, and collectively these effects are going to impair our body’s response to COVID-19 infection or the vaccine,” says Dr. Wallace.

However, experts still urge patients to get the vaccine, because some protection is better than none.

You may be able to schedule your vaccine and medication in a way that leads to a greater immune response. For example, the American College of Rheumatology recommends scheduling vaccination so that the series is initiated about four weeks before the next scheduled rituximab cycle, and delaying rituximab two to four weeks after the final vaccine dose, if disease activity allows. It also recommends holding JAK inhibitors for one week after each vaccine dose.

“Any decisions about whether to switch therapies or to delay infusions should be done on a case-by-case scenario with the rheumatologist or another prescriber of the medication,” says Dr. Sparks. “Perhaps patients could be monitored off the medication or there could be other medications to replace the need for rituximab. But it’s going to be hard to give a blanket statement that would apply to everyone, because certainly this medication is needed for many underlying rheumatic diseases.”

Patients on rituximab or JAKi who become infected with COVID-19 may also consider monoclonal antibody treatment early in the infection to improve their disease course.

Dr. Sparks notes that since this research only looked at rheumatoid arthritis patients, it’s unclear how these medications would affect COVID-19 outcomes with other diseases.

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